Spray-drying apparatus and methods of using the same

ABSTRACT

A spray-drying apparatus includes a drying chamber that has a first end, a second end, and at least one side wall extending between the first and second ends to define an interior of the drying chamber having a center axis. A nozzle can be positioned at the first end of the drying chamber and be configured to atomize liquid and spray the atomized liquid into the interior of the drying chamber at a maximum spray pattern angle relative to the center axis. A heating device can be provided to heat the liquid prior to introduction into the drying chamber.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/820,494, filed Mar. 1, 2013, which is the U.S. National Stage ofInternational Application No. PCT/US2011/050218, filed Sep. 1, 2011,published in English under PCT Article 21(2), which claims the benefitof and priority to U.S. Provisional Patent Application No. 61/380,103filed on Sep. 3, 2010, and U.S. Provisional Patent Application No.61/386,316 filed on Sep. 24, 2010, each of which are incorporated hereinin their entirety by reference.

FIELD

The present disclosure is directed to novel spray-drying apparatuses andmethods of using the same.

BACKGROUND

The use of spray drying to produce powders from fluid feed stocks iswell known, with applications ranging from powdered milk to bulkchemicals and pharmaceuticals. A typical spray-drying apparatuscomprises a drying chamber, an atomizing means for atomizing asolvent-containing feed into the drying chamber, a drying gas that flowsinto the drying chamber to remove solvent from the atomizedsolvent-containing feed, and a product collection means locateddownstream of the drying chamber.

The use of spray drying to form solid amorphous dispersions of drugs oractive agents and concentration-enhancing polymers is also known. Whenit is desired to form a spray-dried product in which the drug or activeagent is amorphous, it is desirable to have the active agent fullydissolved in the spray solution when it is atomized into droplets.Specifically, when it is desired to form a spray-dried product in whichthe amorphous active agent is dispersed in one or more other materials,termed matrix material, it is generally desired to have at least a partand often all of the matrix material also dissolved in the spraysolution. In such cases, the throughput of a conventional spray-dryingprocess is often limited by the amount of active agent and matrixmaterial that can be dissolved in the spray solution. It is generallyknown that the solubility of many substances, such as active agents andmatrix materials, often increases as the temperature of the solvent isincreased. However, industry avoids using elevated temperatures whenusing organic solvents, due to the inherent dangers and safety concernswhen processing organic solvents, which are often flammable at hightemperatures. In addition, conventional spray-drying processes avoid useof elevated temperatures out of concern for the thermal stability of theactive agent and matrix material—degradation of the active agent and/orthe matrix material can lead to unwanted breakdown products in theparticles produced.

Because of this, conventional spray-drying solutions are generally keptat or near room temperature when entering the spray nozzle. This limitsthe throughput of the process due to the often low solubility of activeagents and matrix materials in the solvents used. In addition, when thesolubility of the active agent in the spray solution is low, the activeagent is often dissolved to near its solubility limit to achieve as higha throughput as possible. The spray-dried products obtained from suchsolutions are often not homogeneous. Finally, conventional spray-driedprocesses often produce products that suffer from not being homogeneousbecause the rate of solvent removal is not sufficiently fast, and broadranges of particle sizes are produced because the atomization meansproduces a wide range of droplet sizes.

SUMMARY

In one embodiment, a spray-drying apparatus is provided. The apparatusincludes a drying-gas conduit and a drying chamber having a first end,second end, and at least one side wall extending between the first andsecond ends to define an interior of the drying chamber having a centralaxis. A nozzle can be positioned at the first end of the drying chamber.The nozzle can be configured to atomize a liquid and spray the atomizedliquid into the interior of the drying chamber. The drying-gas conduitis in fluid communication with the drying chamber, and is configured todirect a flow of drying gas into the drying chamber. At least a portionof the at least one side wall that surrounds the nozzle at the first endof the drying chamber extends away from the center axis at a first anglerelative to the center axis, the first angle being at least 5 degreesbut less than 45 degrees. A ratio of the length between the first andsecond ends to a maximum width between opposing internal surfaces of theinterior of the drying chamber is at least 5 to 1.

In one embodiment, a spray-drying apparatus is provided. The apparatusincludes a drying-gas conduit and a drying chamber having a first end,second end, and at least one side wall extending between the first andsecond ends to define an interior of the drying chamber having a centralaxis. A nozzle can be positioned at the first end of the drying chamber.The nozzle can be configured to atomize a liquid and spray the atomizedliquid into the interior of the drying chamber. The drying-gas conduitis in fluid communication with the drying chamber, and is configured todirect a flow of drying gas to enter the drying chamber in substantiallyparallel flow. At least a portion of the at least one side wall thatsurrounds the nozzle at the first end of the drying chamber extends awayfrom the center axis at a first angle relative to the center axis, thefirst angle being at least 5 degrees but less than 45 degrees. A ratioof the length between the first and second ends to a maximum widthbetween opposing internal surfaces of the interior of the drying chamberis at least 5 to 1.

In certain embodiments, the drying gas entering the drying chambersatisfies at least one of (a) the velocity vector of the drying gasaveraged over the opposing internal surfaces of the interior of thedrying chamber is essentially parallel to the center axis of the dryingchamber and is substantially towards the second end of the dryingchamber; and (b) circulation cells near the first end of the dryingchamber in the vicinity of the nozzle have diameters of less than 20% ofthe maximum width between opposing internal surfaces of the interior ofthe drying chamber. In certain embodiments, the drying gas entering thedrying chamber satisfies both (a) and (b).

In certain embodiments, the walls of the drying gas conduit aregenerally parallel to the walls of the drying chamber.

In certain embodiments, the ratio of the length between the first andsecond ends to a maximum width between opposing internal surfaces of theinterior of the drying chamber is at least 6 to 1.

In certain embodiments, a ratio of the maximum width to the width at thesecond end of the drying chamber interior is less than 3 to 1.

In certain embodiments, the nozzle is configured to atomize a liquidinto the drying chamber at a maximum spray pattern angle relative to thecenter axis of less than 45 degrees.

In certain embodiments, the first angle is at least 5 degrees but lessthan 30 degrees relative to the center axis. In certain embodiments, thenozzle is configured to atomize a liquid into the drying chamber at amaximum spray pattern angle relative to the center axis of less than 30degrees.

In certain embodiments, the first angle is at least 5 degrees but lessthan 20 degrees relative to the center axis. In certain embodiments, thenozzle is configured to atomize a liquid into the drying chamber at amaximum spray pattern angle relative to the center axis of less than 20degrees. In certain embodiments, the first angle is at least 10 degreesbut less than 20 degrees relative to the center axis.

In certain embodiments, the at least one side wall of the drying chamberfurther comprises a second tapered portion at the second end, and thesecond tapered portion is narrowest at the second end and widest at adistance furthest from the second end.

In certain embodiments, the at least one side wall of the drying chamberfurther comprises a cylindrical portion of generally constant widthlocated between the first and second tapered portions. In certainembodiments, the at least one side wall of the drying chamber has agenerally circular cross section at each point along the center axisbetween the first end and the second end.

In certain embodiments, the atomized liquid comprises at least oneactive agent and at least one excipient. In certain embodiments, theatomized liquid comprises an active agent and at least one excipient ina solvent.

In certain embodiments, the atomized liquid can form particles that havea mass median aerodynamic diameter of less than 50 microns. In someembodiments, the particles have a mass median aerodynamic diameter ofless than 20 microns. In some embodiments the particles can have a massmedian aerodynamic diameter of less than 10 microns. In yet otherembodiments, the particles can have a mass median aerodynamic diameterof less than 5 microns. In some embodiments, the particles can beinhalable particles.

In another embodiment, a method of spray drying is provided. The methodcan include forming a plurality of particles by atomizing a spraysolution using a nozzle positioned at the first end of the dryingchamber. The drying chamber comprises a second end and at least one sidewall extending between the first and second ends to define an interiorof the drying chamber having a center axis. At least a portion of the atleast one side wall that surrounds the nozzle at the first end of thedrying chamber extends away from a center axis of the drying chamber ata first angle relative to the center axis. The first angle can be atleast 5 degrees but less than 45 degrees. A ratio of the length betweenthe first and second ends to a maximum width between opposing internalsurfaces of the interior of the drying chamber is at least 5 to 1. Theatomized spray solution is delivered into the drying chamber and a flowof drying gas is delivered into the drying chamber to at least partiallydry the atomized spray solution to form a plurality of particles. Theplurality of particles are directed out of the drying chamber.

In another embodiment, a method of spray drying is provided. The methodcan include forming a plurality of particles by atomizing a spraysolution using a nozzle positioned at the first end of the dryingchamber. The drying chamber comprises a second end and at least one sidewall extending between the first and second ends to define an interiorof the drying chamber having a center axis. At least a portion of the atleast one side wall that surrounds the nozzle at the first end of thedrying chamber extends away from a center axis of the drying chamber ata first angle relative to the center axis. The first angle can be atleast 5 degrees but less than 45 degrees. A ratio of the length betweenthe first and second ends to a maximum width between opposing internalsurfaces of the interior of the drying chamber is at least 5 to 1. Theatomized spray solution is delivered into the drying chamber and a flowof drying gas is delivered into the drying chamber in substantiallyparallel flow to at least partially dry the atomized spray solution toform a plurality of particles. The plurality of particles are directedout of the drying chamber.

In some embodiments, the atomized spray solution can be delivered intothe drying chamber at a maximum spray pattern angle relative to thecenter axis of less than 45 degrees. In some embodiments, the atomizedspray solution is delivered into the drying chamber at a maximum spraypattern angle relative to the center axis of less than 30 degrees. Insome embodiments, the atomized spray solution is delivered into thedrying chamber at a maximum spray pattern angle relative to the centeraxis of less than 20 degrees.

In some embodiments, the first angle is at least 5 degrees but less than30 degrees relative to the center axis. In other embodiments, the firstangle is at least 5 degrees but less than 20 degrees relative to thecenter axis.

In other embodiments, the spray solution comprises at least oneexcipient. In yet other embodiments, the particles formed in the dryingchamber have a mass median aerodynamic diameter of less than 10 microns.In some embodiments, the particles can be inhalable particles.

In other embodiments, the particles can have a mean particle residencetime of less than 10 seconds, or in other embodiments, less than 8seconds, less than 5 seconds, or less than 3 seconds.

In another embodiment, a process for increasing the throughput of aspray drier comprises (a) delivering a spray solution comprising anactive agent and a matrix material in an organic solvent to aspray-drying apparatus, (b) atomizing the spray solution into dropletswithin the spray-drying apparatus to remove at least a portion of theorganic solvent from the droplets to form a plurality of particles, and(c) collecting the particles. The spray solution is formed by forming afeed suspension comprising the active agent, the matrix material, andthe organic solvent, wherein the feed suspension is at a temperature T₁,and directing the feed suspension to a heat exchanger, therebyincreasing the temperature of the feed suspension to a temperature T₂,wherein (i) temperature T₂ is greater than temperature T₁, and (ii) thespray solution is at a pressure that is greater than the vapor pressureof the solvent at temperature T₂, such that substantially all of theactive agent in the spray solution and at least a portion of the matrixmaterial are soluble in the solvent at temperature T₂.

In one embodiment, temperature T₂ is greater than the ambient-pressureboiling point of the organic solvent.

In another embodiment, the nozzle used for atomization of the spraysolution is a pressure nozzle. In another embodiment, the nozzle usedfor atomization of the spray solution in the spray-drying apparatus is aflash nozzle. A flash nozzle utilizes a pressure drop that inducescavitation in the spray solution prior to exiting the nozzle orifice toinduce droplet formation. A sweep gas around the orifice is used toeliminate or reduce solids build-up during operation.

In another aspect, the matrix material comprises a polymer. In stillanother aspect, the particles comprise a solid amorphous dispersion ofthe active agent and a polymer.

In another embodiment, a process of spray drying includes delivering aspray solution to a spray-drying apparatus. The spray drying apparatuscomprises a drying chamber with a first end, a second end, and at leastone side wall extending between the first and second ends to define aninterior of the drying chamber and having a center axis. The spraysolution is initially at a temperature T₁ and the delivering of thespray solution to the spray-drying apparatus further comprises directingthe spray solution to a heat exchanger to increase the temperature ofthe spray solution to a temperature T₂, wherein temperature T₂ isgreater than temperature T₁. The method includes forming a plurality ofdroplets by atomizing a spray solution using a nozzle positioned at thefirst end of the drying chamber and delivering the plurality of dropletsinto the drying chamber. The drying chamber comprises a second end andat least one side wall extending between the first and second ends todefine an interior of the drying chamber and having a center axis. Atleast a portion of the at least one side wall that surrounds the nozzleat the first end of the drying chamber extends away from the center axisat a first angle relative to the center axis. The first angle is atleast 5 degrees but less than 45 degrees. A ratio of the length betweenthe first and second ends of the drying chamber to a maximum widthbetween opposing internal surfaces of the interior of the drying chamberis at least 5 to 1. A drying gas is delivered into the drying chamber toat least partially dry the plurality of droplets to form a plurality ofparticles and the plurality of particles are directed out of the dryingchamber.

In another embodiment, a process of spray drying includes forming aplurality of droplets by atomizing a spray solution using a nozzlepositioned at the first end of the drying chamber and delivering theplurality of droplets into the drying chamber. The drying chambercomprises a second end and at least one side wall extending between thefirst and second ends to define an interior of the drying chamber andhaving a center axis. At least a portion of the at least one side wallthat surrounds the nozzle at the first end of the drying chamber extendsaway from the center axis at a first angle relative to the center axis.The first angle being at least 5 degrees but less than 45 degrees and aratio of the length between the first and second ends of the dryingchamber to a maximum width between opposing internal surfaces of theinterior of the drying chamber is at least 5 to 1. Drying gas isdelivered into the drying chamber in substantially parallel flow to atleast partially dry the plurality of droplets to form a plurality ofparticles. The plurality of particles are directed out of the dryingchamber. The spray solution is initially at a temperature T₁ and isdirected to a heat exchanger to increase the temperature of the spraysolution to temperature T₂ prior to atomization of the spray solution,wherein temperature T₂ is greater than temperature T₁.

In some embodiments, a velocity vector of the drying gas entering thedrying chamber averaged over the opposing internal surfaces of theinterior of the drying chamber is essentially parallel to the centeraxis of the drying chamber and is substantially toward the second end ofthe drying chamber. In other embodiments, any circulation cells near thefirst end of the drying chamber in the vicinity of the nozzle havediameters of less than 20% of the maximum width between opposinginternal surfaces of the interior of the drying chamber in the vicinityof the circulation cells.

In other embodiments, a velocity vector of the drying gas entering thedrying chamber averaged over the opposing internal surfaces of theinterior of the drying chamber is essentially parallel to the centeraxis of the drying chamber and is substantially toward the second end ofthe drying chamber. Any circulation cells near the first end of thedrying chamber in the vicinity of the nozzle have diameters of less than20% of the maximum width between opposing internal surfaces of theinterior of the drying chamber.

In some embodiments, the spray solution is a suspension comprising asolute and a solvent. In some embodiments, the spray solution can be ata pressure that is greater than the vapor pressure of the solvent attemperature T₂. In other embodiments, the spray solution is delivered tothe nozzle at a temperature T₃, and temperature T₃ is less than or equalto temperature T₂. In other embodiments, the drying gas forms drying gasstreamlines at the first end of the drying chamber that are toward thesecond end of the drying chamber, and the streamlines have vectors thatare between the vector formed by the center axis of the drying chamberand the vector defined by the walls of the drying chamber.

In other embodiments, the droplets are delivered into the drying chamberat a maximum spray pattern angle relative to the center axis of lessthan 45 degrees. In some embodiments, the first angle is at least 5degrees but less than 30 degrees relative to the center axis. In someembodiments, the nozzle can be configured to atomize a liquid into thedrying chamber at a maximum spray pattern angle relative to the centeraxis of less than 30 degrees. In some embodiments, the first angle is atleast 5 degrees but less than 20 degrees relative to the center axis. Insome embodiments, droplets are delivered into the drying chamber at amaximum spray pattern angle relative to the center axis of less than 20degrees.

In some embodiments, the nozzle is a flash nozzle, with the flash nozzlecomprising a central tube and an outer tube. The spray solution isdelivered through the central tube and a sweep gas being deliveredthrough the outer tube. In some embodiments, the central tube has afirst outer diameter and a first inner diameter at an inlet, and asecond outer diameter and a second inner diameter at an outlet. Thefirst outer diameter is greater than the second outer diameter. Thefirst inner diameter and the second inner diameter are substantially thesame. In some embodiments, the central tube has an inner diameter and anouter diameter, forming a wall thickness of the central tube. In oneembodiment, the wall thickness of the central tube at the inlet isgreater than the wall thickness of the central tube at the outlet.

In some embodiments, the spray solution comprises an active agent and anexcipient. In one embodiment, a spray solution comprises colloidalmaterials, dissolve materials, and mixtures thereof. In someembodiments, the spray solution does not comprise a suspension, meaningthat the spray solution does not contain crystalline or solid materialshaving diameters greater than 1000 nm. In this embodiment, the spraysolution comprises dissolved materials, colloidal materials, andmixtures thereof. In another embodiment, the spray solution comprisesdissolved materials.

In another embodiment, a method of spray drying includes forming a feedsuspension comprising an active agent, a matrix material and a solvent.A spray solution can be formed by directing the feed suspension to aheat exchanger, thereby increasing the temperature of the feedsuspension from a first temperature T₁ to a second temperature T₂ thatis greater than temperature T₁. The spray solution can be at a pressurethat is greater than the vapor pressure of the solvent at temperatureT₂. The spray solution can be delivered to a nozzle positioned at afirst end of a drying chamber, with the drying chamber furthercomprising a second end and at least one side wall extending between thefirst and second ends to define an interior of the drying chamber andhaving a center axis. At least a portion of the at least one side wallthat surrounds the nozzle at the first end of the drying chamber canextend away from the center axis at a first angle relative to the centeraxis that is between 5 degrees and 45 degrees. A plurality of dropletscan be formed by atomizing the spray solution using the nozzle anddelivering the plurality of droplets into the drying chamber at an anglethat is equal to or less than the first angle. A drying gas can bedelivered into the drying chamber to at least partially dry theplurality of droplets to form a plurality of particles and the pluralityof particles can be directed out of the drying chamber. In someembodiments, a ratio of the length between the first and second ends ofthe drying chamber to a maximum width between opposing internal surfacesof the interior of the drying chamber is at least 5 to 1.

In some embodiments, the solvent comprises an organic solvent.

In another embodiment, a process for producing a composition comprisesforming a feed suspension comprising an active agent, a matrix materialand a solvent, wherein the feed suspension is at a temperature T₁. Aspray solution can be formed by directing the feed suspension to a heatexchanger, thereby increasing the temperature of the feed suspension toa temperature T₂, wherein temperature T₂ is greater than temperature T₁,the spray solution is at a pressure that is greater than the vaporpressure of the solvent at temperature T₂, and the active agent and thematrix material are soluble in the solvent at temperature T₂. The spraysolution can be directed to a spray-drying apparatus that comprises adrying chamber, a nozzle, and a source of heated drying gas. The dryingchamber can have a first end, a second, and at least one side wallextending between the first and second ends to define an interior of thedrying chamber. The drying chamber can have a ratio of the lengthbetween the first and second ends of the drying chamber to a maximumwidth between opposing internal surfaces of the interior of the dryingchamber that is at least 5 to 1. The nozzle can be configured to atomizethe spray solution into droplets. The spray solution can be atomizedinto droplets in the drying chamber by the nozzle, with the spraysolution being delivered to the nozzle at a temperature T₃. The dropletscan be contacted with the heated drying gas to remove at least a portionof the solvent from the droplets to form a plurality of particlescomprising the active agent and the matrix material, and the particlescan be collected.

In another embodiment, a spray-drying apparatus comprises a feedsuspension tank for storing a feed suspension and a heating deviceconfigured to heat the feed suspension to form a spray solution. Theapparatus can also include a drying-gas conduit, a drying chamber, and anozzle positioned at the first end of the drying chamber. The can beconfigured to atomize the spray solution and spray the atomized spraysolution into the interior of the drying chamber. The drying chamber canhave a first end, a second end, and at least one side wall extendingbetween the first and second ends to define an interior of the dryingchamber having a center axis. The drying-gas conduit can be in fluidcommunication with the drying chamber and configured to direct a flow ofdrying gas into the drying chamber. At least a portion of the at leastone side wall that surrounds the nozzle at the first end of the dryingchamber extends away from the center axis at a first angle relative tothe center axis, with the first angle being at least 5 degrees but lessthan 45 degrees.

In some embodiments, a ratio of the length between the first and secondends of the drying chamber to a maximum width between opposing internalsurfaces of the interior of the drying chamber is at least 5 to 1. Insome embodiments, the heating device is a heat exchanger coupled betweenwith the feed suspension tank and the nozzle. The heat exchanger caninclude a feed suspension inlet and a spray solution outlet.

The disclosed processes provide one or more advantages over aconventional spray-drying process. Certain embodiments of the disclosedprocesses can increase the throughput of a spray dryer by forming aspray solution that has a higher concentration at a higher temperaturethan conventional processes. For example, a higher degree of homogeneityand more uniform particle size can be provided, which improves thethroughput of spray-drying equipment and provides a safe, reproducibleprocess to produce high-quality product.

Certain embodiments of the disclosed processes can increase thethroughput of a spray dryer by forming a spray solution that has ahigher concentration at a higher temperature than conventionalprocesses. Operating in this regime generally leads to spray-driedproducts that are more homogeneous and more uniform. In addition, thedisclosed processes result in rapid evaporation of the solvent andshorter times to solidification than conventional processes.Furthermore, in some embodiments, the process results in improvedatomization of the spray solution relative to conventional processes dueto the temperature of the spray solution when it is atomized being abovethe boiling point of the solvent at the pressure of the drying chamber.

The foregoing and other objects, features, and advantages of thedisclosed embodiments will become more apparent from the followingdetailed description, which proceeds with reference to the accompanyingfigures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a spray-drying apparatus.

FIG. 2 is an enlarged cross-sectional view of one embodiment of a dryingchamber.

FIG. 3 is a side view of an embodiment of the drying chamber of aspray-drying apparatus.

FIG. 4 shows velocity contours for one embodiment of the spray-dryingapparatus.

FIG. 5 is an enlarged view of a portion of a drying chamber, shown witha nozzle delivering atomized spray solution into the drying chamber.

FIG. 6 is an enlarged view of another embodiment of a drying chamber,shown with a nozzle delivering atomized spray solution into the dryingchamber.

FIG. 7 illustrates another embodiment of a drying chamber.

FIG. 8 is a graph illustrating particle residence time in a dryingchamber of a spray-drying apparatus as described herein.

FIG. 9 is a schematic of a spray-drying apparatus suitable for use inperforming a process of a disclosed embodiment.

FIG. 10 is a schematic of a flash nozzle, suitable for use withembodiments of spray-drying apparatuses disclosed herein.

FIG. 11 is a figure showing the results of powder X-ray diffraction ofthe samples of Example 10, Control 1, and Control 2.

FIG. 12 is a schematic view of a spray-drying apparatus.

DETAILED DESCRIPTION

Various embodiments of spray-drying apparatuses and their methods of useare disclosed herein. The following description is exemplary in natureand is not intended to limit the scope, applicability, or configurationof the invention in any way. Various changes to the described embodimentmay be made in the function and arrangement of the elements describedherein without departing from the scope of the invention.

As used in this application and in the claims, the singular forms “a,”“an,” and “the” include the plural forms unless the context clearlydictates otherwise. Additionally, the term “includes” means “comprises.”Further, the term “coupled” generally means electrically,electromagnetically, and/or physically (e.g., mechanically orchemically) coupled or linked and does not exclude the presence ofintermediate elements between the coupled or associated items absentspecific contrary language.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, percentages,measurements, distances, ratios, and so forth, as used in thespecification or claims are to be understood as being modified by theterm “about.” Accordingly, unless otherwise indicated, implicitly orexplicitly, the numerical parameters set forth are approximations thatmay depend on the desired properties sought and/or limits of detectionunder standard test conditions/methods. When directly and explicitlydistinguishing embodiments from discussed prior art, the embodimentnumbers are not approximates unless the word “about” is recited.

Although the operations of exemplary embodiments of the disclosed methodmay be described in a particular, sequential order for convenientpresentation, it should be understood that disclosed embodiments canencompass an order of operations other than the particular, sequentialorder disclosed. For example, operations described sequentially may insome cases be rearranged or performed concurrently. Further,descriptions and disclosures provided in association with one particularembodiment are not limited to that embodiment, and may be applied to anyembodiment disclosed.

As used herein, the terms matrix material and excipient may be usedinterchangeably. Matrix materials and excipients may be consideredsolutes. In some embodiments, the term solutes includes active agents.In other embodiments, the term solutes includes at least one activeagent and at least one matrix material. In other embodiments, the termsolutes includes at least one active agent and at least one excipient.

Conventional spray-drying apparatuses require a drying chamber of arelatively large diameter to provide the desired throughput of fluidfeed stock. These large diameter drying chambers can be relativelyexpensive to manufacture and operate due to increased air handling,utility, and construction costs. Also, the combination of the largedrying chamber and the manner in which drying gas enters the chamberresults in non-parallel gas flow with large circulation cells. Such gasflow patterns can carry particles to the chamber wall before completedrying, can lead to long residence times, and can even result inparticles contacting hot gas and hot metal surfaces near the drying gasentrance.

In addition, particle residence times in these large drying chambers canbe quite long and variable, causing at least some particles to beexposed to elevated temperatures and elevated solvent concentrations,which can damage or reduce the efficacies of active agents in theparticles. The particle residence time distributions in large dryingchambers can also be quite broad, leading to large differences inparticle properties within a single batch of spray dried powder. Anapparatus with a smaller diameter and with substantially parallel flowin the vicinity of the spray nozzle results in shorter particleresidence times, and a much narrower particle residence timedistribution, resulting in more uniform particle properties.

The collection efficiencies of conventional larger diameter dryingchambers can also be relatively poor, due to the lower pressuresmaintained in these larger diameter drying chambers, especially whenspray drying particles with relatively small diameters, such as thosewith diameters of 10 μm or less. In addition, the larger diameter ofconventional spray-drying apparatuses leads to a high surface area andhigh surface area to volume ratios, and a corresponding high heat loss.An apparatus with a smaller diameter and correspondingly smaller surfacearea and/or surface to volume ratio, can reduce heat loss, making thespray drying process more efficient. The larger diameter of conventionalspray-drying apparatuses leads to large drying-chamber volumes, makingoperation at elevated pressures expensive due to the increased strengthrequired to maintain a large volume under elevated pressure. By using arelatively small volume drying chamber, higher pressures can be achievedwithin the drying chamber, resulting in lower capital costs, and higherparticle collection efficiencies. Conventional spray drying apparatusesalso require a large room to accommodate all the equipment. By using asmall volume drying chamber, the room space required is greatly reduced,further reducing capital costs required for installation and operationof the spray dryer. The larger diameters and higher surface areas ofconventional spray-drying apparatuses also leads to large amounts ofcleaning agents required after each use and when changing from oneproduct to another. Thus, a smaller diameter dryer with a smallersurface area can reduce the amount of cleaning agents required by thespray-drying system.

Accordingly, there is a need for an improved spray-drying apparatusdesign that results in the production of spray-dried solids with lowerequipment costs, exposure of particles to lower maximum temperatures,shorter duration of exposure to elevated temperatures, more uniformdrying conditions for all droplets and particles, and improvedcollection efficiency.

In particular, the combination of (1) a smaller volume, larger aspectratio drying chamber, (2) atomization of the liquid to be dried suchthat the droplets are directed parallel to or away from the dryingchamber walls, (3) introduction of the drying gas such that it entersthe drying chamber in a uniform flow pattern that is substantiallyparallel to the center axis of the drying chamber, and/or (4)construction of the drying gas conduit and drying chamber such thatthere are few gas circulation cells, results in extremely efficientdrying, uniform and relatively short exposure of droplets and particlesto heat and solvent vapors, and high product recovery.

An embodiment of the disclosed spray-drying apparatus is shown inFIG. 1. Although the following embodiments illustrate spray-dryingapparatuses that are generally circular in cross section, it should beunderstood that unless contrary to the disclosed processes herein, theapparatus can take any other cross-sectional shapes suitable for spraydrying a spray solution, including, for example, square, rectangular,and octagonal shapes, among others.

As shown in FIG. 1, spray-drying apparatus 10 can comprise a dryingchamber 40, a nozzle 50, and a particle collection member 60. In oneembodiment, the spray-drying apparatus 10 can be utilized as follows. Aspray solution 26 can be formed by mixing a solute with a solvent. Inone embodiment, the spray solution may be stored in a feed tank (notshown in FIG. 1). The spray solution may be kept homogenous using amixing means (also not shown in FIG. 1). In another embodiment, thespray solution may be prepared continuously.

As used herein, the term “spray solution” means a composition includinga solute and a solvent. The term “solute” means a material that isdesired to be spray dried. In one embodiment, the solute comprises atleast one active agent. In another embodiment, the solute comprises atleast one excipient. In still another embodiment, the solute comprises amixture of at least one active agent and at least one excipient.

In one embodiment, the spray solution 26 comprises an active agent and asolvent. In another embodiment, the spray solution 26 comprises anexcipient and a solvent. In still another embodiment, the spray solution26 comprises an active agent, at least one excipient, and a solvent. Thespray solution 26 can include, for example, mixtures, solutions, and/orsuspensions. For example, in one embodiment, the active agent can bedissolved in the solvent. In another embodiment, a portion of the activeagent can be suspended or not dissolved in the solvent. In anotherembodiment, the active agent can be dissolved in the solvent, while aportion of an excipient is dissolved in the solvent. In anotherembodiment, a portion of the active agent, a portion of an excipient, ora portion of both an active agent and an excipient can be suspended ornot dissolved in the solvent.

In one embodiment, the spray solution 26 consists essentially of anactive agent, at least one excipient, and a solvent. In still anotherembodiment, the spray solution consists of an active agent, at least oneexcipient, and a solvent. In yet another embodiment, the spray solutionconsists of particles of active agent suspended in a solution of atleast one excipient dissolved in the solvent. In yet another embodiment,the spray solution also contains particles of one or more excipientssuspended in the solution. It will be recognized that in such spraysolutions, a portion of the active agent and the one or more excipientsmay dissolve up to their solubility limits at the temperature of thespray solution.

As used herein, “active agent” means a drug, medicament, pharmaceutical,therapeutic agent, nutraceutical, nutrient, or other compound. Theactive agent may be a “small molecule,” generally having a molecularweight of 2000 Daltons or less. The active agent may also be a“biological active.” Biological actives include proteins, antibodies,antibody fragments, peptides, oligoneucleotides, vaccines, and variousderivatives of such materials. In one embodiment, the active agent is asmall molecule. In another embodiment, the active agent is a biologicalactive. In still another embodiment, the active agent is a mixture of asmall molecule and a biological active. In yet another embodiment, thecompositions made by certain of the disclosed processes comprise two ormore active agents.

As used herein, the term “feed suspension” means a compositioncomprising an active agent, a matrix material, and a solvent, wherein atleast a portion of the active agent, a portion of the matrix material,or a portion of both active agent and matrix material are suspended ornot dissolved in the solvent. In some embodiments, the solvent is anorganic solvent. In one embodiment, the feed suspension consistsessentially of an active agent, a matrix material, and a solvent. Instill another embodiment, the feed suspension consists of an activeagent, a matrix material, and a solvent. In yet another embodiment, thefeed suspension consists of particles of active agent suspended in asolution of matrix material dissolved in the solvent. It will berecognized that in such feed suspensions, a portion of the active agentand the matrix material may dissolve up to their solubility limits atthe temperature of the feed suspension.

As used herein, the term “solvent” means water or other compounds, suchas an organic compound, that can be used to dissolve or suspend thesolute. In one embodiment, the solvent is volatile, having anambient-pressure boiling point of 150° C. or less. In anotherembodiment, the solvent has an ambient-pressure boiling point of 100° C.or less. Suitable solvents can include water; alcohols such as methanol,ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone,methyl ethyl ketone and methyl isobutyl ketone; esters such as ethylacetate and propyl acetate; and various other solvents, such astetrahydrofuran, acetonitrile, methylene chloride, toluene, and1,1,1-trichloroethane. Lower volatility solvents such asdimethylacetamide or dimethylsulfoxide can also be used, generally incombination with a volatile solvent. Mixtures of solvents, such as 50%methanol and 50% acetone, can also be used, as can mixtures with water.

As used herein, the term “organic solvent” means a solvent that is anorganic compound. In one embodiment, the solvent is volatile, having anambient-pressure boiling point of 150° C. or less. In anotherembodiment, the solvent has an ambient-pressure boiling point of 100° C.or less. Suitable solvents include alcohols such as methanol, ethanol,n-propanol, isopropanol, and butanol; ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; esters such as ethyl acetateand propyl acetate; and various other solvents, such as tetrahydrofuran,acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane.Lower volatility solvents such as dimethylacetamide or dimethylsulfoxidecan also be used, generally in combination with a volatile solvent.Mixtures of solvents, such as 50% methanol and 50% acetone, can also beused, as can mixtures with water. In one embodiment, the organic solventcontains less than 50 wt % water. In another embodiment, the organicsolvent contains less than 25 wt % water. In still another embodiment,the organic solvent contains less than 10 wt % water. In yet anotherembodiment, the organic solvent contains less than 5 wt % water. Inanother embodiment, the organic solvent contains essentially no water.

As used herein, the term “excipient” means a substance that may bebeneficial to include in a composition with an active agent. The term“excipient” includes inert substances as well as functional excipientsthat may result in beneficial properties of the composition. Exemplaryexcipients include but are not limited to polymers, sugars, salts,buffers, fats, fillers, disintegrating agents, binders, surfactants,high surface area substrates, flavorants, carriers, matrix materials,and so forth.

The spray solution can be delivered to a nozzle 50 via a pump or otherdelivery device (not shown). Nozzle 50 atomizes the spray solution intothe drying chamber in the form of droplets 44. Drying gas 42 flowsthrough a drying-gas conduit 41, which is in fluid communication withthe first end 70 of drying chamber 40. In one embodiment, the first end70 of the drying chamber is located at the position where the spraysolution exits the nozzle 50. In one embodiment, the drying-gas conduit41 is configured to allow the drying gas 42 to enter the drying chamber40 with substantially parallel flow. As used herein, “substantiallyparallel flow” means that the flow of drying gas 42 entering the dryingchamber satisfies at least one of the following two conditions. First,the velocity vector of the drying gas 42 averaged over the cross-sectionof the first end 70 of the drying chamber 40 is essentially parallel tothe center axis of drying chamber 40 and is substantially towards thesecond end 72 of drying chamber 40. Second, any circulation cells nearthe first end 70 of the drying chamber 40 in the vicinity of nozzle 50are small, with the diameter of the circulation cells being less than20% of the maximum width between opposing internal surfaces of theinterior of the drying chamber 40 in the area of the circulation cell.As used herein, “essentially parallel” means that the velocity vectoraveraged over the cross-section of the first end 70 of the dryingchamber 40 has a direction that ranges between the center axis of thedrying chamber and the angle formed by the walls 48 and the center axisat the first end 70. In one embodiment, the drying gas entering thedrying chamber meets both of these conditions.

In another embodiment, the drying gas streamlines, defined as the localgas velocity vectors, are essentially all directed from the first end 70of the drying chamber 40 toward the second end 72 of the drying chamber40. In addition, these drying gas streamlines have vectors that arebetween the vector defined by the center axis of the drying chamber 40and the vectors defined by the walls 48 of the drying chamber.

To achieve substantially parallel flow, the drying-gas conduit 41 andfirst end 70 should generally be free from sharp surfaces or protrusionsthat could significantly disrupt the flow of the drying gas 42. Inaddition, the walls of the drying gas conduit 41 and the drying chamber40 should be generally parallel to each other where the drying gasconduit 41 is coupled to the drying chamber 40, particularly when it iscoupled in the vicinity of the nozzle. As used in this context herein,“generally parallel” means that an angle formed between the walls of thegas conduit and drying chamber relative to the center axis of the dryingchamber 40 is less than 45 degrees. In one embodiment, the drying-gasconduit 41 contains at least one flow straightener, such as a mesh,screen, or perforated plate that results in substantially parallel flowwhen the drying gas 42 enters the drying chamber 40. In anotherembodiment, the drying gas conduit 41 is smooth, having a radius ofcurvature that is at least twice the width between opposing side wallsat the first end 70 of the drying chamber 40.

The drying gas 42 is combined with the droplets 44 in the drying chamber40. In the drying chamber 40, at least a portion of the solvent isremoved from the droplets 44 to form an exiting fluid 46 comprisingevaporated solvent and drying gas 62 and a plurality of at leastpartially dried particles 66. The term “exiting fluid” refers to anyfluids, particles, or combinations of fluids and particles that exit thedrying chamber 40.

The exiting fluid 46 exits the drying chamber at the second end 72through exit conduit 49, and can be directed to a particle collectionmember 60. Suitable particle collection members include cyclones,filters, electrostatic particle collectors, and the like. In theparticle collection member 60, the evaporated solvent and drying gas 62can be separated from the plurality of particles 66, allowing forcollection of the particles 66.

As shown in FIGS. 1 and 3, drying chamber 40 has a first end 70 and asecond end 72. First end 70 can be an inlet for receiving the nozzle andcan be coupled to the drying gas conduit 41 for receiving the drying gas42. Second end 72 can be an outlet that can be coupled to an exitconduit 49, and then to a particle collection member 60 or other suchdevice to receive and collect the particles as they exit drying chamber40. The interior volume of drying chamber 40 can be defined by one ormore side walls 48 that extend between first and second ends 70, 72. Ifdrying chamber 40 comprises a single integral structure, a single sidewall 48 can extend from first end 70 to second end 72. Alternatively,drying chamber 40 can be formed of sections that include multiple sidewalls 48 that are coupled together to form a single drying chamber.

In one embodiment, the first end 70 of the drying chamber 40 is locatedwhere the spray solution exits the nozzle 50 via one or more outlets inthe nozzle 50, while the second end 72 is located where the exit conduit49 starts.

FIG. 2 shows an enlarged cross-sectional view of an embodiment of thefirst end 70 of drying chamber 40. Nozzle 50 can be centrally positionedat first end 70 of drying chamber 40 along the center axis E-E′ of thedrying chamber, which generally extends longitudinally along the centeraxis of drying chamber 40. Nozzle 50 can have a spray pattern such thatdroplets 44 are directed out of nozzle 50 at a maximum spray angle A1.Angle A1 can be equal to an angle A2 formed between center axis E-E′ anda side wall 48 of drying chamber 40 that is adjacent to or in thevicinity of nozzle 50. In one embodiment, angles A1 and A2 are generallyequal, that is, within about 5 degrees of one another. Drying gas 42enters the drying chamber 40 via drying gas conduit 41 with an exitcenter axis E-E″. In one embodiment, drying gas conduit 41 exit centeraxis E-E″ is parallel to the center axis of the drying chamber E-E′. Inanother embodiment, E-E″ and E-E′ are approximately coincident.

Generally, the temperature and flow rate of the drying gas should bechosen so that the droplets of spray solution are dry enough by the timethey reach the wall of the apparatus that, at least on the particlesurface, they are essentially solid, form a fine powder, and do notstick to the apparatus wall. The actual length of time to achieve thislevel of dryness depends on the size of the droplets and the conditionsat which the process is operated. In conventional systems, droplets exitthe nozzle and are directed on a range of trajectories such that many oftheir trajectories are towards the side walls. In addition to increasingresidence time, directing droplets towards the side walls requires thatthe distance from the nozzle to the side wall be sufficiently large sothat the ejected droplets have enough time to dry, at least on thesurface of the droplets, before contacting the side wall. By providing anozzle and angled side wall as shown in FIG. 1, however, the width(e.g., diameter) of the spray-drying apparatus can be reduced since thedroplets are directed generally parallel to the side wall. Accordingly,by forming angles A1 and A2 generally equal to one another, droplets canbe provided with sufficient time to dry, without requiring a wide dryingchamber.

One of ordinary skill will understand that the required length of theangled side wall will be a function of (1) the droplet diameter, (2) thedroplet velocity, (3) the drying gas velocity, and (4) the time for thedroplet to become sufficiently dry on the surface so that the particledoesn't stick to the walls of the drying chamber. Generally, largerdroplet diameters will require longer lengths of the angled side wall toensure the droplet is sufficiently dry before contacting the interiorwalls of the drying chamber.

To the extent that one of angles A1 and A2 are different, angle A1 issomewhat smaller than angle A2 to reduce the chance that atomized spraysolution or particles will contact the side wall of the drying chamber.

Accordingly, if the maximum spray angle A1 does not exceed the angle A2formed by side wall 48, droplets or particles exiting nozzle 50 aredirected away from or parallel to the side wall and not towards sidewall 48. To substantially direct the droplets in a direction generallyparallel to the side wall of the drying chamber, angle A1 is 45 degreesor less. Angle A1 can also be 40 degrees or less, 35 degrees or less, 30degrees or less, 25 degrees or less, 20 degrees or less, 15 degrees orless, 10 degrees or less, or 5 degrees or less.

As shown in FIGS. 1 and 2, droplets ejected from nozzle 50 with amaximum spray pattern of 45 degrees or less can be directed along a paththat generally does not intersect with side wall 48 that is adjacent toor in the vicinity of nozzle 50. In the illustrated embodiment of FIG.2, angle A1 is 15 degrees.

As described above, in one embodiment, angle A2 is substantially equalto angle A1. Thus, if angle A2 is equal to 30 degrees and nozzle 50 hasa maximum spray angle A1 that is equal to or less than 30 degrees,droplets 44 are directed away from or along (i.e., parallel to) theinner surface of side wall 48 and generally prevented from contactingthe side wall of the drying chamber. In the illustrated embodiment ofFIG. 2, angle A1 is 15 degrees and angle A2 is substantially equal to A1(i.e., angle A2 is about 15 degrees).

FIG. 3 shows a cross-section of an embodiment of drying chamber 40.Position A is the inlet (first end 70) and Position D is the outlet(second end 72) of drying chamber 40. As shown in other embodiments, anozzle can be located at or near position A. In this embodiment, thedrying chamber includes three main sections. Section A-B is an expandingtapered section, Section B-C is a straight section, and Section C-D is acontracting tapered section. In one embodiment, the expanding taperedsection A-B can be 75-100 cm long and can be narrowest at the inlet end(Position A) and widest at a position furthest from the inlet end. Thestraight section B-C can be 25-50 cm long and can have a substantiallyconstant width along its length. The contracting tapered section C-D canbe 25-50 cm long and can be narrowest at the outlet end (second end 72,Position D) and widest at a position furthest from the second end 72.Accordingly, in one embodiment, a total length of the drying chamber(i.e., the length of section A-B+the length of section B-C+the length ofsection C-D) can vary from 125 cm to 200 cm. One of ordinary skill willunderstand that drying chambers with other lengths and widths can beconstructed and be within the scope of the invention, and the inventionis not limited to the lengths and widths described above.

The three sections can be separate side walls 48 that are coupled orconnected together in any conventional manner (e.g., mechanically and/orchemically). Alternatively, the three sections can be integrally formedof a single side wall member.

In the embodiment shown in FIG. 3, the width of the apparatus is 25.4 cm(10 inches). The width at any point along the length of the dryingchamber is the distance between opposing internal surfaces of the sidewall(s). Thus, the ratio of the length to the maximum width of thedrying chamber is at least 5 to 1 (e.g., the length is at least 125 cmif the width is 25 cm) and can even be greater than 6 to 1. In oneembodiment, the ratio of the length to the maximum width of the dryingchamber can be even greater, such as 10 to 1, or more. By providing adrying chamber that has a length that is significantly greater than itswidth, residence time in the drying chamber can be greatly reduced.Instead of being captured and recirculated within the drying chamber,droplets or particles ejected from the nozzle are directed towards thesecond end 72 and out of the drying chamber 40 through exit conduit 49.The substantial length (relative to the width) provides enough time forthe droplets or particles to be sufficiently dried before exiting thedrying chamber.

In one embodiment, section A-B can be 86.4 cm (34 inches) long andtappers from 7.6 cm (3 inches) wide at Position A to 25.4 cm (10 inches)wide at Position B. The straight section B-C can be 40.6 cm (16 inches)long. The contracting tapered section C-D can be 40.6 cm (16 inches)long and tappers from 25.4 cm (10 inches) wide at Position C to 10.2 cm(4 inches) wide at Position D. Thus, in this specific implementation,the ratio of the length to the maximum width of the drying chamber is6.6 to 1 (i.e., 167.6 cm to 25.4 cm).

In addition, in the above embodiment, although the second end 72 has anopening with a smaller diameter (10 cm) than the diameter of the maximumwidth between opposing surfaces of the interior of the drying chamber(25 cm), the ratio of the maximum width between opposing surfaces of theinterior of the drying chamber to the diameter at the second end of thedrying chamber interior is less than 6 to 1. In other embodiments, theratio of the maximum width between opposing surfaces of the interior ofthe drying chamber to the diameter at the second end of the dryingchamber interior may be less than 5 to 1, less than 4 to 1, less than 3to 1, or even less than 2.5 to 1. Generally, to aid in the collection ofparticles, the ratio of the maximum width between opposing surfaces ofthe interior of the drying chamber to the diameter at the second end ofthe drying chamber interior should be greater than 1.1 to 1.

In one embodiment of FIG. 3, the apparatus has a generally cylindricalshape. The first end of the drying chamber (70) is located at PositionA. The second end of the drying chamber (72) is located at Position D.The cylindrical walls of the drying chamber (48) define an interior ofthe drying chamber having a center axis. The nozzle is located at ornear the first end (70) of the drying chamber at Position A. A portionof the cylindrical walls of the drying chamber (48) extends away fromthe center axis at a first angel relative to the center axis (SectionA-B). The drying chamber further comprises a cylindrical portion ofgenerally constant width at Section B-C. The drying chamber furthercomprises a second tapered portion (Section C-D) at the second end (72)that is narrowest at the second end (72, Position D), and widest atPosition C. The ratio of the length between the first end (70) and thesecond end (72) (that is, the length between Positions A and D) to themaximum width between opposing internal surfaces of the interior of thedrying chamber (that is, at Position B) is at least 5 to 1. In oneembodiment, a ratio of the maximum width (at Position B) to the width atthe second end (72) of the drying chamber (at Position D) is less than 3to 1.

In one embodiment, the plurality of particles produced in theapparatuses disclosed herein are inhalable particles that can be inhaledby a subject (e.g., human or animal). As used herein, the term“inhalation” refers to delivery to a subject through the mouth or nose.In one embodiment, the spray-dried particles are delivered to the “upperairways.” The term “upper airways” refers to delivery to nasal, oral,pharyngeal, and laryngeal passages, including the nose, mouth,nasopharynx, oropharynx, and larynx. In another embodiment, thespray-dried particles are delivered to the “lower airways.” The term“lower airways” refers to delivery to the trachea, bronchi, bronchioles,alveolar ducts, alveolar sacs, and alveoli.

In one embodiment, the particles have a mass median aerodynamic diameter(MMAD) of about 5 to 100 μm. In another embodiment, the particles have aMMAD of about 10 to 70 μm. Mass median aerodynamic diameter (MMAD) isthe median aerodynamic diameter based on particle mass. In a sample ofparticles, 50% of the particles by weight will have an aerodynamicdiameter greater than the MMAD, and 50% of the particles by weight willhave an aerodynamic diameter smaller than the MMAD. In yet anotherembodiment, the particles have an average diameter of 50 μm, or even 40μm, or 30 μm. In other embodiments, the particles can have an MMAD ofless than about 20 μm, or even less than about 10 μm. In anotherembodiment, the particles have a MMAD ranging from 0.5 μm to 10 μm. Instill another embodiment, the particles have a MMAD ranging from 1 μm to5 μm.

In one embodiment, the particles are intended for inhalation and have aMMAD of 0.5 to 100 μm. In another embodiment, the particles are intendedfor inhalation and have a MMAD of 0.5 to 70 μm.

In one embodiment, the particles are intended for delivery to the upperairways, and have a MMAD of greater than 10 μm. In another embodiment,the particles are intended for delivery to the upper airways and have aMMAD of 10 to 100 μm, and wherein the weight fraction of particleshaving an aerodynamic diameter of less than 10 μm is less than 0.1. Inanother embodiment, the particles are intended for delivery to the upperairways and have a MMAD of 10 to 70 μm, and the weight fraction ofparticles having an aerodynamic diameter of less than 10 μm is less than0.1.

In another embodiment, the particles are intended for delivery to thelower airways, and have a MMAD of less than 10 μm. In one embodiment,the particles are intended for delivery to the lower airways, and have aMMAD of 0.5 to 10 μm, and the weight fraction of particles having anaerodynamic diameter of greater than 10 μm is less than 0.1. In anotherembodiment, the particles are intended for delivery to the lowerairways, and have a MMAD of 0.5 to 7 μm, and the weight fraction ofparticles having an aerodynamic diameter of greater than 7 μm is lessthan 0.1.

In some embodiments of inhalable particles, the active agent comprises adrug, medicament, pharmaceutical, therapeutic agent, nutraceutical,nutrient, or other compound suitable for treating, diagnosing,preventing, or otherwise affecting a particular physical condition orstate of the patient.

Inhalable particles formed using the spray-drying apparatuses describedherein can be dispersed in an inhalation device, such as an inhaler,without producing significant amounts of one or more of the followingundesirable side effects when administered via inhalation to a subject:cough, emesis, toxic build-up in the lung, inflammation, reduced lungfunction. One measure of lung function is the FEV₁ (forced expiratoryvolume in one second) test, which measures the volume exhaled during thefirst second of a forced expiratory maneuver started from the level oftotal lung capacity.

In one embodiment, the concentration of solvent remaining in theparticles when they are collected (that is, the concentration ofresidual solvent) is less than 10 wt % based on the total weight of theparticles (i.e., the combined weight of the particle and solvent). Inanother embodiment, the concentration of residual solvent in theparticles when they are collected is less than 5 wt %. In yet anotherembodiment, the concentration of residual solvent in the particles isless than 3 wt %. In another embodiment, a drying process subsequent tothe spray-drying process may be used to remove residual solvent from theparticles. Exemplary processes include tray drying, fluid-bed drying,vacuum drying, and other similar drying processes.

The drying gas may be virtually any gas, but to minimize the risk offire or explosions due to ignition of flammable vapors, and to minimizeundesirable oxidation of the active agent or other excipients, an inertgas such as nitrogen, nitrogen-enriched air, helium, or argon isutilized. The temperature of the drying gas at the gas inlet ofapparatus 10 is typically from 20° to 300° C. The temperature of theproduct particles, drying gas, and evaporated solvent in the exitingfluid 46 typically ranges from 0° C. to 100° C.

By selecting a nozzle with a relatively small spray pattern angle (e.g.,30 degrees or less as measured relative to a central axis of the dryingchamber) and providing a spray-drying chamber that generally encompassesonly the space required to contain the spray plume contour of thenozzle, spray-dried solids can be produced satisfactorily withsignificantly smaller equipment. The smaller amount of space requiredfor the spray-drying apparatuses disclosed herein relative toconventional spray-drying equipment, results in lower construction andutility costs (room size, air handling, etc.). In addition, the smallersize of the spray dryer allows it to be more easily enclosed incommercially available isolators, reducing operator exposure to highlypotent compounds or aerosolized particles that can present an inhalationrisk. This provides operators improved safety by further reducingpotentially hazardous airborne particles.

The design also minimizes the amount of product buildup on the insidesurfaces of the drying chamber, which improves production efficiency byreducing the amount of down time that is required for cleaning thedrying chamber. By directing all particles generally parallel to theside walls—rather than directly towards the side walls as is the case inconventional spray-drying systems—few or none contact the side wall.Moreover, by directing a drying gas into the drying chamber in themanner shown in FIG. 6, even fewer particles contact the side wallssince the drying gas further directs the droplets in a directiongenerally parallel to the side wall. Thus, by using the spray-dryingapparatuses described herein, few, if any, droplets contact the sidewalls of the drying chamber, thereby reducing the amount of effortneeded to clean the side walls.

In certain embodiments, the interior of the drying chamber has a volumethat is 80 L or less, or even less than 70 L. In one embodiment, thedrying chamber has a volume of between 55-65 L. By using a relativelysmall volume drying chamber, higher pressures can be achieved within thedrying chamber. For example, a drying gas can be delivered into thedrying chamber at 1200-1500 g/min, or even at 1300-1400 g/min. Thetemperature and type of gas can vary; however, temperatures of between100 and 180 degrees Celsius are typical, with temperatures between 135and 160 degrees Celsius being common. The small volume of the dryingchamber in combination with the pressure of the drying gas results inhigh particle collection efficiencies at the second end of the dryingchamber, as well as low residence times which can provide a number ofbenefits as described herein.

In one embodiment, the mean particle residence time of the spray-dryingapparatuses disclosed herein can be less than 10 seconds. Shorterresidence times can be obtained, and are sometimes desirable, such asless than 8 seconds, less than 5 seconds, or less than 3 seconds. Incomparison, conventional spray-drying equipment often has residencetimes of 20 to 40 seconds for similar spray solution flow rates. Thereduced particle residence time for the disclosed apparatuses reducesexposure to elevated drying gas temperatures that can cause degradationof active agents or excipients, allowing heat-sensitive materials to bespray dried. For example, compounds such as DNA, proteins, or antibodiesthat are not stable for long periods of time in a spray-drying chamberat high temperature and humidity, can be dried using the apparatusesdisclosed herein due to the order of magnitude smaller residence time.

In addition to reducing the potential for degradation of active agents,shorter residence times also allow for the generation of a moreconsistent end product. Recirculation can cause widely varying residencetimes, which can result in large inconsistencies in particles as theyexit the drying chamber. By reducing residence times and the relatedrecirculation associated with longer residence times, spray-driedparticles can be created with more consistent and predictableattributes, and with a narrower particle size distribution. Suchconsistency can be particularly important when spray-dryingpharmaceutical compositions, such as the inhalable particles describedherein. Thus, the spray-drying apparatuses disclosed herein can produceinhalable particles with a reduced variability in particle size andpharmacological activity. For example, Table 3 below illustrates thelower “Span” (a dimensionless parameter indicative of the uniformity ofparticle size distribution as described in more detail below) andimproved fine particle fraction (FPF) of particles produced using aspray-drying apparatus as shown in FIG. 1 relative to conventionalspray-drying systems.

FIG. 8 illustrates particle residence time in a drying chamber using aspray-drying apparatus as shown in FIG. 1. In particular, FIG. 8 showsthe cumulative percentage of particles removed from the drying chamberover time. As shown in FIG. 8, when actively directing atomized spraysolution into the drying chamber, 50% of all particles can be removedfrom the drying chamber within 2 seconds, 80% of all particles can beremoved from the drying chamber within 3 seconds, 90% of all particlescan be removed from the drying chamber within 4 seconds, and more than95% of all particles can be removed from the drying chamber within 6seconds, and 100% of all particles can be removed from the dryingchamber within 8 seconds.

An additional advantage of the spray-drying apparatuses disclosed hereinis found in the collection of small particles. For spray-dryingparticles having diameters of less than 10 μm using conventionalspray-drying equipment, collection efficiency can be particularly poor.As discussed above, the smaller volume chambers of the spray-dryingapparatuses disclosed herein can allow a higher operating pressure,resulting in more efficient particle collection in a cyclone.

FIG. 4 shows velocity contours for droplets and particles in oneembodiment of the spray-drying chamber. The data in FIG. 4 illustratesthat the droplets and particles move substantially parallel to the wallsof the spray-drying chamber and contact with the walls by droplets orparticles that have not been substantially dried is substantiallyprevented.

FIG. 5 illustrates an enlarged view of a nozzle 50 extending into adrying chamber 40. As described above, nozzle 50 can be generallyaligned along a center axis of drying chamber 40. Drying gas 42 can bedirected into drying chamber 40 and around nozzle 50. In one embodiment,one or more screens can be used to help maintain the central position ofnozzle 50 within drying chamber 40. For example, as shown in FIG. 6,first and second mesh screen members 57, 59 can be positioned within thedrying gas inlet member to secure nozzle 50 in the desired centralposition. Mesh screen members 57 and 59 may also be used to help producesubstantially parallel flow of the drying gas when it enters the dryingchamber 40.

FIG. 7 illustrates another embodiment of a spray-drying apparatus 100.Spray-drying apparatus 100 is generally similar to spray-dryingapparatus 10. Instead of the three distinct regions (A-B, B-C, C-D)shown in FIG. 1, however, spray-drying apparatus 100 has a continuouscurvature along the length of the side wall of the drying chamber 102.Like spray-drying apparatus 10, drying chamber 102 can increase in widthfrom a first end 104 towards the center of drying chamber 102 and thendecrease in width at a second end 106. Spray-drying apparatus 100, shownin FIG. 7, can have the same general dimensions (e.g., length, maximumand minimum widths, volume) as spray-drying apparatus 10. As describedin more detail in the other embodiments, a nozzle can be coupled orsecured at first end 104, and a collection member can be coupled orsecured to second end 106 to capture at least partially dried particlesas they exit the drying chamber 102.

As described above, the spray-drying apparatuses described herein areparticularly suitable for producing particles of small averagediameters, such as those suitable for inhalation (e.g., less than 10μm). In other embodiments, however, the particles formed by thespray-drying apparatuses described herein can have an average diameterranging from 0.5 μm to 500 μm. In another embodiment, the particles havea diameter ranging from 0.5 μm to 100 μm. In another embodiment, theparticles have an average diameter of greater than 10 μm. In stillanother embodiment, the particles have an average diameter of greaterthan 20 μm. In still another embodiment, the particles have an averagediameter of greater than 30 μm.

Spray-Dried Solid Compositions

In one embodiment, the spray-dried product formed by the spray-dryingapparatus can comprise an active agent. In another embodiment, thespray-dried product formed by the spray-drying apparatus can comprise anexcipient. In another embodiment, the spray-dried product formed by thespray-drying apparatus can comprise an active agent and at least oneexcipient. The excipient can be used to dilute the active and/or modifythe properties of the composition. For instance, for inhalationapplications, an excipient may improve or slow the rate of particledissolution in lung fluid, lung fluid, bronchial mucus, or nasal mucus,reduce particle agglomeration, and/or improve reproducibility of theemitted dose. Examples of excipients include but are not limited tosynthetic polymers, polysaccharides, derivatized polysaccharides,sugars, sugar alcohols, organic acids, salts of organic acids, inorganicsalts, proteins, amino acids, phospholipids, and pharmaceuticallyacceptable salt forms, derivatives, and mixtures thereof. In anotherembodiment, the excipient is selected from polyvinyl pyrrolidone (PVP),polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate),polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castoroils, polycaprolactam, polylactic acid, polyglycolic acid,poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran,maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate,heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate(HPMCAS), ethyl cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, dextran polymer derivatives, trehalose,glucose, sucrose, raffinose, lactose, mannitol, erythritol, xylitol,polydextrose, oleic acid, citric acid, tartaric acid, edetic acid, malicacid, sodium citrate, sodium bicarbonate, albumin, gelatin, acacia,casein, caseinate, glycine, leucine, serine, alanine, isoleucine,tri-leucine, lecithin, phosphatidylcholine, and pharmaceuticallyacceptable forms, derivatives, and mixtures thereof. In one embodiment,the excipient is selected from lactose, mannitol, trehalose, sucrose,citric acid, leucine, glycine, dextran, oleic acid, and pharmaceuticallyacceptable salt forms, derivatives, and mixtures thereof. In stillanother embodiment, the excipient is selected from lactose, mannitol,trehalose, sucrose, citric acid, leucine, glycine, and pharmaceuticallyacceptable salt forms, derivatives, and mixtures thereof.

The apparatus can be used to form a wide variety of pharmaceuticalcompositions, including, but not limited to, spray dried amorphous drug,spray dried solid amorphous dispersions, amorphous drug absorbed to ahigh-surface area substrate, spray dried crystalline drug in a matrix,microparticles, nanoparticles, and spray-dried excipients.

EXAMPLES Actives Used in Examples

Active Agent 1 was4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol, alsoknown as salbutamol sulfate, having the structure:

Active Agent 1 is freely soluble in water, and a Log P value of 0.11.The glass-transition temperature (T_(g)) of amorphous Active Agent 1 wasdetermined by DSC to be 125° C.

Active Agent 2 was insulin, a heterotetrameric protein with a pKa of5.39, Log P 0.22, and melting temperature (T_(m)) of 81° C.

Active Agent 3 was Peptide YY (PYY), a novel 36 amino-acid amidatedhormone available from GenScript USA Inc. The peptide is soluble inwater.

Example 1 Active Agent 1: Dextran 10

A dry powder consisting of particles of a solid dispersion of ActiveAgent 1 was prepared by forming a spray solution containing 0.5 wt %Active Agent 1, 1.5 wt % Dextran 10 (Dextran having a molecular weightof 10,000 daltons, available from Amersham Sciences, Piscataway, N.J.),and 98.0 wt % water as follows: the active and solvent were combined ina 500 mL flask and mixed to form a clear solution, then the polymer wasadded to the solution and mixed for 30 minutes.

The spray solution was pressure fed using 30 psi nitrogen pressure feedfrom a 1 L pressure vessel to a 2-fluid nozzle (Spray Systems 1650liquid, 120 air cap). Liquid feed was 25 mL/min, and atomizing nitrogenwas 3.0 SCFM at 42 psi into an apparatus substantially similar to thatshown in FIG. 1. The inlet nitrogen gas at a flow of 1340 g/min washeated to 155° C. and introduced to the spray dryer. The exittemperature of the drying gas was 55° C. The dried material waspneumatically conveyed through reducing-sized ductwork to a 3-inchoutside diameter cyclone. The resulting solid dispersion particles werecollected in a 20 mL jar attached to the bottom of the cyclone. Theevaporated solvent and drying gas exited the dryer through the top ofthe cyclone, and were conditioned by a filter and scrubber. The 5.1 gcollected of so-formed solid dispersion particles were then dried undervacuum desiccation at room temperature.

Dispersion particles were characterized using a Malvern Particle SizeAnalyzer, available from Malvern Instruments Ltd. of Framingham, Mass.The data obtained includes D₁₀, the diameter corresponding to thediameter of particles that make up 10% of the total volume containingparticles of equal or smaller diameter, and D₉₀, the diametercorresponding to the diameter of particles that make up 90% of the totalvolume containing particles of equal or smaller diameter. Anotherparameter is “Span,” defined as

${{Span} = \frac{D_{90} - D_{10}}{D_{50}}},$(where D₅₀ is the diameter corresponding to the diameter of particlesthat make up 50% of the total volume containing particles of equal ofsmaller diameter). Span, sometimes referred to in the art as theRelative Span Factor or RSF, is a dimensionless parameter indicative ofthe uniformity of the particle size distribution. Generally, the lowerthe Span, the more narrow the particle size distribution, resulting inimproved flow characteristics. The result of the Span determinationusing Malvern analysis for Example 1 is shown in Table 1.

In Vitro Inhalation Performance

The dry powder was also characterized using the NEXT GENERATIONPHARMACEUTICAL IMPACTOR (NGI), Model 170 (available from MSPCorporation, Shoreview, Minn.). The NGI was equipped with a Copleyventilator set at 60 L/min flow for 4 seconds, to draw the spray driedpowder into chambers representing the lungs. NGI data include massmedian aerodynamic diameter (MMAD) and fine particle fraction (FPF-NGIstages 3 to 8 representing “deep lungs”, <4.6 μm)—the fraction ofparticles that would deposit in the deep lungs, or alveoli. The activedose deposited in the lung can be calculated by multiplying the emitteddose (e.g., the dose delivered by an inhalation device) by the fineparticle fraction (deposited dose=emitted dose×FPF).

A 15 mg sample of the solid dispersion particles was evaluated using theNGI. The sample was weighed and loaded into a Quali-V HPMC capsule (size#3). In each chamber of the NGI, 3 drops of silicon oil were added anddistributed to all surfaces using a Kimwipe. The HPMC capsule waspunctured and attached to the NGI mouth. The chambers were rinsed using10 mL deionized water, and the samples analyzed using HPLC. The resultsof the NGI evaluation for Example 1 are shown in Table 1.

Differential Scanning Calorimetry (DSC)

DSC was used to measure the glass transition temperature. The soliddispersion samples were equilibrated for a minimum of 14 hours atambient temperature and <5% RH, and at ambient temperature and 50% RH.Sample pans were crimped and sealed in an environmental chamber, thenloaded into a Thermal Analysis Q1000 Differential Scanning calorimeterequipped with an autosampler (available from T_(A) Instruments, NewCastle, Del.). The samples were heated by modulating the temperature at±1.5° C./min, and ramping the temperature up to 200° C. at 2.5° C./min.The sample had a single Tg at 125° C. and no other thermal events,suggesting the composition was amorphous.

TABLE 1 NGI data Malvern Dry Data Example FPF* (%) MMAD** (μm) Span 1 792.6 1.62 *FPF—fine particle fraction **MMAD—mass median aerodynamicdiameter

Example 2 Active Agent 1: Dextran 10

A dry powder consisting of particles of a solid dispersion of ActiveAgent 1 was prepared by forming a spray solution containing 1.5 wt %Active 1, 0.5 wt % Dextran 10, and 98.0 wt % water as follows: theactive and solvent were combined in a 500 mL flask and mixed to form aclear solution, then the polymer was added to the solution and mixed for30 minutes.

The spray solution was pressure fed using 30 psi nitrogen pressure feedfrom a 1 L pressure vessel to a 2-fluid nozzle (Spray Systems 1650liquid, 120 air cap). Liquid feed was 25 mL/min, and atomizing nitrogenwas 3.0 SCFM at 42 psi into an apparatus substantially the same as theapparatus shown in FIG. 1. The inlet nitrogen gas at a flow of 1340g/min was heated to 151° C. and introduced to the spray dryer. The exittemperature of the drying gas was 55° C. The dried material waspneumatically conveyed through reducing-sized ductwork to a 3-inchoutside diameter cyclone. The resulting solid dispersion particles werecollected in a 20 mL jar attached to the bottom of the cyclone. Theevaporated solvent and drying gas exited the dryer through the top ofthe cyclone, and were conditioned by a filter and scrubber. The 5.4 g ofso-formed solid dispersion particles were then dried under vacuumdesiccation at room temperature.

Dispersion particles were characterized using the Malvern Particle SizeAnalyzer, and the results are shown in Table 2.

In Vitro Inhalation Performance

The dry powder was tested using the NEXT GENERATION PHARMACEUTICALIMPACTOR (NGI), as described above. The results of the NGI evaluationfor Example 2 are shown in Table 2.

Differential Scanning Calorimetry (DSC)

DSC was used to measure the glass transition temperature. The soliddispersion samples were equilibrated for a minimum of 14 hours atambient temperature and <5% RH, and at ambient temperature and 50% RH,and analyzed as described above. The sample had a single Tg at 123° C.and no other thermal events, suggesting the composition was amorphous.

TABLE 2 Example NGI data Malvern Dry Data SDD FPF* (%) MMAD** (μm) Span2 74 2.6 1.50 *FPF—fine particle fraction **MMAD—mass median aerodynamicdiameter

Examples 3-5 Active Agent 2: Dextran 10

Examples 3-5 were solid dispersions consisting of 70 wt % Active Agent 2and 30 wt % Dextran 10. To make Examples 3-5, spray solutions containing2.1 wt % Active 2, 0.9 wt % Dextran 10, and 97.0 wt % 0.01 Nhydrochloric acid were formed by combining the active agent and solventin a 125 mL flask, mixing to form a clear solution, and adding thepolymer with stirring. The pH of the spray solution was adjusted to 7.4using dilute sodium hydroxide. Prior to spray drying, the solution wasdiluted with water. For Examples 3 and 4, the final solids concentrationin the spray solution was 0.2 wt %. For Example 5, the final solidsconcentration in the spray solution was 0.8 wt %.

To spray dry the dispersions, the spray solutions were pressure fedusing 30 psi nitrogen pressure feed from a 1 L pressure vessel to a2-fluid nozzle (Spray Systems 1650 liquid, 120 air cap). Liquid feed was12 mL/min for Example 3, and 25 mL/min for Examples 4 and 5. Atomizingnitrogen was 3.4, 3.5, and 3.6 SCFM (Example 3, 4, and 5) at 52, 56, and60 psi (Example 3, 4, and 5) into an apparatus substantially the same asthat shown in FIG. 1. For Example 3, the inlet nitrogen gas (1320 g/min)was heated to 110° C. and introduced to the spray dryer. For Examples 4and 5, the inlet nitrogen gas (1350 g/min) was heated to 140° C. andintroduced to the spray dryer. The exit temperature of the drying gasfor Examples 3, 4, and 5 was 55° C. The dried material was pneumaticallyconveyed through reducing-sized ductwork to a 3-inch OD cyclone. Theresulting solid dispersion particles were collected in a 20 mL jarattached to the bottom of the cyclone. The evaporated solvent and dryinggas exited the dryer through the top of the cyclone, and wereconditioned by a filter and scrubber. The solid dispersion particleswere then dried under vacuum desiccation at room temperature.

Dispersion particles were characterized using the Malvern Particle SizeAnalyzer, and the results are shown in Table 3.

In Vitro Inhalation Performance

The dry powders were tested using the NGI as described above. Theresults of the NGI evaluation for Examples 3, 4, and 5 are shown inTable 3.

Controls 1 and 2 Active Agent 2: Dextran 10

Controls 1 and 2 were solid dispersions consisting of 70 wt % ActiveAgent 2 and 30 wt % Dextran 10, spray-dried as described above, exceptthat a conventional spray dryer was used. To make Controls 1 and 2,spray solutions containing 2.1 wt % Active 2, 0.9 wt % Dextran 10, and97.0 wt % 0.01 N hydrochloric acid were formed as described above forExamples 3-5. The dispersion of Control 1 was spray-dried withoutdilution (3.0 wt % solids), and the dispersion of Control 2 wasspray-dried following dilution of the spray solution by addition ofwater, for a final solids concentration of 0.8 wt %. The solutions werespray-dried by directing an atomizing spray using a two-fluidexternal-mix spray nozzle (Spray Systems 1650 liquid, 120 air cap) at afeed rate of 12.5 g/min into the stainless-steel chamber of a spraydryer (a Niro type XP Portable Spray-Drier with a Liquid-Feed ProcessVessel (“PSD-1”)), maintained at a temperature of 130° C. at the inlet.The resulting solid dispersions were collected in a cyclone. Thedispersions formed using the above procedure were post-dried beforefurther use.

Dispersion particles were characterized using the Malvern Particle SizeAnalyzer and the NGI, and the results are shown in Table 3. The resultsin Table 3 show that dispersion particles obtained using the PSD-1 arelarger, with a larger span (broader particle size distribution) thandispersion particles obtained using the spray-drying apparatusesdisclosed herein. Example 5 and Control 2 provide the closestcomparisons, since these dispersions were spray-dried from spraysolutions both containing 0.8 wt % solids.

TABLE 3 Malvern Dry Example NGI data Data SDD FPF* (%) MMAD** (μm) Span3 90 ND 1.32 4 97 ND 1.11 5 88 1.6 1.28 Control 1 82 2.1 1.51 Control 262 2.6 1.61 *FPF—fine particle fraction **MMAD—mass median aerodynamicdiameter ND—no data

Examples 6 and 7 Active Agent 1: Dextran 10

Examples 6 and 7 were solid dispersions consisting of Active Agent 1 andDextran 10. To make Example 6, a spray solution was formed containing0.1 wt % Active 1, 1.9 wt % Dextran 10, and 98.0 wt % water, giving asolid dispersion consisting of 5 wt % Active Agent 1 and 95 wt % Dextran10. To make Example 7, a spray solution was formed containing 0.2 wt %Active 1, 1.8 wt % Dextran 10, and 98.0 wt % water, giving a soliddispersion consisting of 10 wt % Active Agent 1 and 90 wt % Dextran 10.To spray dry the dispersions, the spray solutions were pressure fedusing 30 psi nitrogen pressure feed from a 1 L pressure vessel to a2-fluid nozzle (Spray Systems 1650 liquid, 120 air cap). Liquid feed was25 mL/min, and atomizing nitrogen was 3.0 SCFM at 42 psi into anapparatus substantially the same as that shown in FIG. 1. The inletnitrogen gas (1350 g/min) was heated to 130° C. for Example 6, and 150°C. for Example 7, and introduced to the spray dryer. The exittemperature of the drying gas was 55° C. The dried material waspneumatically conveyed through reducing-sized ductwork to a 3-inchoutside diameter cyclone. The resulting solid dispersion particles werecollected in a 20 mL jar attached to the bottom of the cyclone. Theevaporated solvent and drying gas exited the drier through the top ofthe cyclone, and were conditioned by a filter and scrubber. The soliddispersion particles were then dried under vacuum desiccation at roomtemperature.

Dispersion particles were characterized using the Malvern Particle SizeAnalyzer and the NGI, and the results are shown in Table 4.

TABLE 4 Malvern Dry Example NGI data Data SDD FPF* (%) MMAD** (μm) Span6 65 2.8 ND 7 69 2.6 2.8 *FPF—fine particle fraction **MMAD—mass medianaerodynamic diameter ND—no data

Examples 8 and 9 Active Agent 3: Dextran 10

Examples 8 and 9 were solid dispersions consisting of 70 wt % ActiveAgent 3 and 30 wt % Dextran 10. To make Example 8, a spray solutioncontaining 2.0 wt % Active 3, 0.9 wt % Dextran 10, and 97.1 wt % waterwas formed by combining the active and solvent in a 125 mL flask, mixingto form a clear solution, and adding the polymer with stifling. The pHof the spray solution was adjusted to 6.4 using dilute sodium hydroxide.Prior to spray drying, the solution was diluted to 1.5 wt % solids withwater. To make Example 9, a spray solution containing 1.0 wt % Active 3,0.4 wt % Dextran 10, and 98.6 wt % water was formed by combining theactive and solvent in a 125 mL flask, mixing to form a clear solution,and adding the polymer with stirring. The pH of the spray solution wasadjusted to 6.6 using dilute sodium hydroxide. There was no dilution ofthe spray solution prior to spray drying. To spray dry the dispersions,the spray solutions were pressure fed using 30 psi nitrogen pressurefeed from a 1 L pressure vessel to a 2-fluid nozzle (Spray Systems 1650liquid, 120 air cap). Liquid feed was 25 mL/min, and atomizing nitrogenwas 3.3 SCFM at 45 psi into an apparatus substantially the same as thatshown in FIG. 1. The inlet nitrogen gas (1350 g/min) was heated to 143°C. for Example 8, and 118° C. for Example 9, and introduced to the spraydryer. The exit temperature of the drying gas was 55° C. The driedmaterial was pneumatically conveyed through reducing-sized ductwork to a3-inch outside diameter cyclone. The resulting solid dispersionparticles were collected in a 20 mL jar attached to the bottom of thecyclone. The evaporated solvent and drying gas exited the drier throughthe top of the cyclone, and were conditioned by a filter and scrubber.The solid dispersion particles were then dried under vacuum desiccationat room temperature.

Dispersion particles were characterized using the NGI, and the resultsare shown in Table 5.

TABLE 5 Example NGI data SDD FPF* (%) MMAD** (μm) 8 80 2.06 9 80 1.84*FPF—fine particle fraction **MMAD—mass median aerodynamic diameter

FIG. 9 illustrates an embodiment of a method and system configured forintroducing spray solutions at elevated temperatures into a dryingchamber. FIG. 9 illustrates the drying chamber 40 of spray-dryingapparatus 110 as being generally cylindrical. However, the dryingchamber may take any other cross-sectional shape suitable for spraydrying a spray solution, including square, rectangular, and octagonal,among others. The spray-drying apparatus 110 is also depicted as havingone nozzle 50. However, multiple nozzles can be included in thespray-drying apparatus to achieve higher throughput of the spraysolution.

Referring to FIG. 9, apparatus 110 includes a feed suspension tank 20, aheat exchanger 30, a drying chamber 40, a nozzle 50, and aparticle-collection means 60. In one embodiment, the process isperformed as follows. An active agent and a matrix material are combinedwith a solvent in the feed suspension tank 20 to form a feed suspension.The solvent can be an organic solvent. The feed suspension is at atemperature T₁, which is below the ambient-pressure boiling point of thesolvent. Temperature T₁ is also below either T_(A), the temperature atwhich the active agent solubility equals the active agent concentrationin the solvent at equilibrium, or T_(M), the temperature at which thematrix material solubility equals the matrix material concentration inthe solvent at equilibrium. One of ordinary skill will understand thatseveral factors affect dissolution of an active agent and a matrixmaterial in a solvent, including the solute particle size, the flowconditions of the suspension, and the residence time of the soluteparticles in the solvent at T_(A) or T_(M). At least a portion of theactive agent, a portion of the matrix material, or a portion of both theactive agent and the matrix material are suspended, that is notdissolved, in the solvent. An optional mixing means 22 may be used tokeep the feed suspension homogeneous while processing. When the solventis flammable, oxygen is normally excluded from all parts of the dryingapparatus. In particular, an inert gas, such as nitrogen, helium, argon,and the like, is often used to fill the void space in the feedsuspension tank for safety reasons.

For convenience, the feed suspension can be maintained at near-ambienttemperatures; however, this is not a limitation of the disclosedprocesses. Generally, the temperature of the feed suspension, T₁, canrange from 0° C. to 50° C. or even higher. Temperatures of less than 0°C. may also be utilized, especially when there are stability concernsabout the active agent.

The feed suspension in the feed suspension tank 20 is delivered to apump 24, which directs the feed suspension to a heating device, such asheat exchanger 30. Heat exchanger 30 has a feed suspension inlet 26, aspray solution outlet 36, a heating fluid inlet 32, and a heating fluidoutlet 34. In the heat exchanger 30, the feed suspension enters throughthe feed suspension inlet 26 at temperature T₁, and exits as the spraysolution through the spray solution outlet 36 at temperature T₂. Spraysolution temperature T₂ is greater than feed suspension temperature T₁.To prevent unwanted vaporization/boiling of the solvent in the spraysolution, pump 24 increases the pressure of the spray solution such thatthe pressure of the spray solution at spray solution outlet 36 isgreater than the vapor pressure of the solvent at temperature T₂. Thetemperature of the spray solution when it enters the nozzle 50 isgenerally near T₂. Preferably it is within 30° C. of temperature T₂. Inaddition, T₂ is greater than or equal to the lesser of T_(A) and T_(M).In one embodiment, T₂ is greater than or equal to the greater of T_(A)and T_(M). When it is the object of the process to form a solidamorphous dispersion of the active agent and the matrix material, T₂ isgreater than or equal to T_(A). Preferably, T₂ is at least 10° C.greater than T_(A). In one embodiment, the spray solution temperature T₂is greater than the ambient-pressure boiling point of the solvent.

The spray solution exiting the heat exchanger may be at any temperature,T₂, which is greater than T₁, as long as T₂ is greater than or equal tothe lesser of T_(A) and T_(M). Temperature T₂ may be at least 10° C.greater than T₁, at least 20° C. greater than T₁, at least 30° C.greater than T₁, at least 40° C. greater than T₁, or even at least 50°C. greater than T₁. In one embodiment, temperature T₂ is at least 50° C.In another embodiment, temperature T₂ is at least 70° C. In anotherembodiment, temperature T₂ is at least 80° C. In another embodiment,temperature T₂ is at least 90° C. In another embodiment, T₂ is at least100° C. In still another embodiment, T₂ is at least 120° C.

In one embodiment, the active agent and the matrix material are bothessentially completely dissolved in the solvent at temperature T₂. By“essentially completely dissolved” is meant that less than 5 wt % of thesolute remains undissolved. In the case of matrix materials, the term“dissolved” can take a broader definition. For some matrix materials,such as polymers, the term dissolved can mean the polymer has gone intosolution, or it can mean the polymer is dispersed or highly swollen withthe solvent such that it acts as if it were in solution. In contrast, attemperature T₁, at least one of the active agent and the matrix materialare present as a suspension in the solvent. Any suitable technique maybe used to determine if the active agent and matrix material are solublein the solvent at temperature T₂. Examples include dynamic or staticlight scattering analysis, turbidity analysis, and visual observations.In one embodiment, the spray solution comprises the active agent and thematrix material dissolved in the solvent at temperature T₂.

In one embodiment, temperature T₂ is greater than the temperature atwhich the active agent and matrix material are soluble in the solvent.That is, T₂ is greater than or equal to the greater of T_(A) and T_(M).It may be desirable that temperature T₂ be much greater than the greaterof T_(A) and T_(M). Thus, temperature T₂ may be at least 10° C. greaterthan the greater of T_(A) and T_(M), at least 20° C. greater than thegreater of T_(A) and T_(M), or even at least 30° C. greater than thegreater of T_(A) and T_(M). Spray-dried products made by embodiments ofthe disclosed processes are typically more uniform and homogeneous whentemperature T₂ is greater than the greater of T_(A) and T_(M).

In one embodiment, the pump 24 increases the pressure of the spraysolution to a pressure ranging from 2 atm to 400 atm. In anotherembodiment, the pressure of the spray solution as it exits the heatexchanger 30 is greater than 10 atm.

The heat exchanger 30 may be of any design wherein heat is transferredto the feed suspension resulting in an increase in temperature. In oneembodiment, the heat exchanger 30 is an indirect heat exchanger, whereina heating fluid is in contact with the feed suspension through aheat-transfer surface. Exemplary indirect heat exchangers includetube-in-tube devices and tube-in-shell devices, both well-known in theart. The heat exchanger 30 may also be a direct heat exchanger, in whicha heating fluid, such as steam, is injected directly into the feedsuspension, resulting in an increase in the temperature of the feedsuspension. In yet another embodiment, the feed suspension flows over ahot surface, such as a resistance heating element, resulting in anincrease in temperature of the feed suspension. Other heating sourcesmay also be used, such as microwaves and ultrasonic devices that canincrease the temperature of the feed suspension.

The concentration of active agent and matrix material in the spraysolution can be virtually any value. In one embodiment, theconcentration of total solids (that is, active agent and matrixmaterial) in the solvent is at least 0.5 wt %. The concentration oftotal solids in the solvent may be at least 1 wt %, at least 5 wt %, oreven at least 10 wt % or more. In another embodiment, the concentrationof active agent in the solvent is at least 1.25-fold the solubility ofthe active agent in the solvent at temperature T₁. The concentration ofactive agent in the solvent may be at least 1.5-fold, at least 2.0-fold,or even 2.5-fold or more the solubility of the active agent in thesolvent at temperature T₁.

In one embodiment, the residence time of the feed suspension in the heatexchanger 30 is minimized so as to limit the time thesuspension/solution is exposed to elevated temperatures. The residencetime of the suspension/solution in the heat exchanger may be less than30 minutes, less than 20 minutes, less than 10 minutes, less than 5minutes, or even less than 1 minute.

The spray solution at the spray solution outlet 36 is directed to adrying chamber 40, where it enters a nozzle 50 for atomizing the spraysolution into droplets 44. The temperature of the spray solution when itenters the nozzle 50 is the spray temperature, designated as T₃. When itis desired to keep the active agent and matrix material dissolved in thespray solution, it is often desirable for T₃ to be at or near T₂.However, there are sometimes advantages to having T₃ significantly lessthan T₂. For example, degradation of the active agent may be reduced oratomization in certain nozzles may be more effective when T₃ issignificantly less than T₂. In some cases, it is even desirable for T₃to be sufficiently low that the active agent, the matrix material, orboth the active agent and the matrix material are not soluble in thesolvent. In such cases, the solution may be below the point at which thesolutes are soluble for a sufficiently short time such that all thesolutes remain in solution until the solution is atomized.Alternatively, the solution may be below the point at which the solutesare soluble for a sufficiently long time that one or more of the matrixmaterial or the active agent may precipitate or crystallize fromsolution. In one embodiment, temperature T₃ is less than 5° C. less thanT₂. In another embodiment, temperature T₃ is less than 20° C. less thanT₂. In another embodiment, temperature T₃ is less than 50° C. less thanT₂. In still another embodiment, both temperatures T₂ and T₃ are greaterthan the greater of T_(A) and T_(M). In one embodiment, temperatures T₂and T₃ are at least 5° C. greater than the greater of T_(A) and T_(M).In another embodiment, temperatures T₂ and T₃ are at least 20° C.greater than the greater of T_(A) and T_(M). In yet another embodiment,temperatures T₂ and T₃ are at least 50° C. greater than the greater ofT_(A) and T_(M).

In one embodiment, the apparatus 110 is designed such that the time thespray solution is at a temperature greater than T₃ is minimized. Thismay be accomplished by locating the spray solution outlet 36 as close aspossible to the nozzle 50. Alternatively, the size of the tubing orfluid connections between the spray solution outlet 36 and the nozzle 50may be small, minimizing the volume of spray solution and reducing thetime the spray solution is at a temperature greater than T₃. The timethe spray solution is at a temperature greater than T₃ may be less than30 minutes, less than 20 minutes, less than 10 minutes, less than 5minutes, or even less than 1 minute.

Virtually any nozzle can be used to atomize the spray solution intodroplets. The inventors have found that pressure nozzles are effectivein embodiments of the disclosed processes. In another embodiment, aflash nozzle is used, as described below.

The drying chamber 40 also has a source of heated drying gas 42 which iscombined with the droplets 44 in the drying chamber 40. In the dryingchamber 40, at least a portion of the solvent is removed from thedroplets to form a plurality of particles comprising the active agentand the matrix material. Generally, it is desired that the droplets aresufficiently dry by the time they come in contact with the dryingchamber surface that they do not stick or coat the chamber surfaces.

The particles, along with the evaporated solvent and drying gas, exitthe drying chamber at outlet 46, and are directed to aparticle-collection means 60. Suitable particle-collection means includecyclones, filters, electrostatic particle collectors, and the like. Inthe particle-collection means 60, the evaporated solvent and drying gas62 are separated from the plurality of particles 66, allowing forcollection of the particles.

The particles may be of any desired size. In one embodiment, theparticles have an average diameter ranging from 0.5 μm to 500 μm. Inanother embodiment, the particles have a diameter ranging from 0.5 μm to100 μm. In another embodiment, the particles have an average diameter ofgreater than 10 μm. In still another embodiment, the particles have anaverage diameter of greater than 20 μm. In still another embodiment, theparticles have an average diameter of greater than 30 μm. In yet anotherembodiment, the particles have a mass median aerodynamic diameterranging from 0.5 μm to 10 μm. In still another embodiment, the particleshave a mass median aerodynamic diameter ranging from 1 μm to 5 μm.

In one embodiment, the concentration of solvent remaining in theparticles when they are collected (that is, the concentration ofresidual solvent) is less than 10 wt % based on the total weight of theparticles. In another embodiment, the concentration of residual solventin the particles when they are collected is less than 5 wt %. In yetanother embodiment, the concentration of residual solvent in theparticles is less than 3 wt %. In another embodiment, a drying processsubsequent to the spray-drying process may be used to remove residualsolvent from the particles. Exemplary processes include tray drying,fluid-bed drying, vacuum drying, and the drying processes described inWO2006/079921 and WO2008/012617.

In one embodiment, nozzle 50 is a flash nozzle 50 a. There is shown inFIG. 10 a cross-sectional schematic of a flash nozzle 50 a. Flash nozzle50 a consists of a central tube 51 and an outer tube 53. Central tube 51is in fluid communication with the inflowing spray solution 55, whileouter tube 53 is in fluid communication with a sweep gas 52. The flashnozzle 50 a has an inlet end, represented by A, and an outlet end,represented by B. The spray solution 55 from the heat exchanger 30 (notshown in FIG. 10) enters central tube 51 at A. A sweep gas 52 entersouter tube 53 at A. As spray solution 55 travels through the centraltube 51 from inlet A to outlet B, the pressure decreases due to pressuredrop. Between the inlet A and outlet B, the pressure of the spraysolution 55 decreases to a value that is less than the vapor pressure ofthe solvent in the spray solution, leading to the formation of vaporbubbles of the solvent (a process known as cavitation). By the time thespray solution 55 reaches outlet B of the central tube 51, it is a fluid56 comprising droplets of spray solution and vapor-phase solvent. In oneembodiment, the central tube 51 is coated with a non-stick coating. Inanother embodiment, the outer tube 53 is coated with a non-stickcoating. In still another embodiment, the central tube 51 and the outertube 53 are coated with a non-stick coating. Non-stick coatings include,for example, polytetrafluoroethylene (PTFE) or other suitable non-stickcoatings.

The sweep gas 52 exiting through the outer tube outlet 58 is in fluidcommunication with the fluid 56 exiting through the central tube 51. Thesweep gas 52 decreases the likelihood that solid material will form atthe exit from the central tube 51 or the outer tube 53.

The processes described herein can be used to form a compositioncomprising an active agent. The active agent can be highly watersoluble, sparingly water soluble, or poorly water soluble. In oneembodiment, the active agent is “poorly water soluble,” meaning that theactive agent has a solubility in water (over the pH range of 6.5 to 7.5at 25° C.) of less than 5 mg/mL. The active agent may have an even loweraqueous solubility, such as less than about 1 mg/mL, less than about 0.1mg/mL, and even less than about 0.01 mg/mL.

The processes disclosed herein can also be used to form compositionscomprising a matrix material. Matrix materials suitable for use in thecompositions formed by the disclosed methods should be inert, in thesense that they do not chemically react with the active agent in anadverse manner. The matrix material can be neutral or ionizable. In oneembodiment, the composition includes two or more matrix materials.

Exemplary matrix materials include polysaccharides. Polysaccharides canbe underivatized, such as cellulose, starch, dextran, pullulan, dextrin,maltodextrin, glycogen, inulin, fructan, mannan, chitin, polydextrose,fleximer (a ring-opened form of dextran), and oligosaccharides. Often,derivatives and substituted versions of the polysaccharides arepreferred. Examples of such polysaccharide derivatives include ester-and ether-linked derivatives. Included in this class are celluloseethers, cellulose esters, and cellulose derivatives that have both esterand ether substituents. Specific examples include cellulose acetate,ethyl cellulose, hydroxypropyl methyl cellulose and hydroxyethylcellulose. Starch derivatives include starch acetate and carboxymethylstarch. Also included are synthetic matrix materials, such aspolyacrylates and polymethacrylates, vinyl matrix materials,polyethylenes, polyoxyethylenes, polypropylenes, polyamides, polyesters,polycarbonates, and derivatives and substituted versions thereof;copolymers of various types, including random and block copolymers;other matrix materials such as lactose, trehalose, sucrose, fructose,maltose, dextrose, xylitol, sorbitol, glycine, amino acids, citric acid,phospholipids, bile salts; and mixtures thereof.

In one embodiment, the matrix material is amphiphilic, meaning that thematrix material has hydrophobic and hydrophilic portions. In anotherembodiment, the matrix material is ionizable.

In yet another embodiment, the matrix material comprises a polymer.Appropriate matrix polymers include polyvinylpyrrolidone, vinylacetate/vinylpyrrolidone copolymers, vinyl alcohol, vinyl acetate/vinylalcohol copolymers, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, carboxymethylcellulose, carboxymethyl ethylcellulose, hydroxypropyl methylcelluloseacetate succinate, cellulose acetate phthalate and cellulose acetatetrimellitate. In still another embodiment, the matrix material comprisesan ionizable cellulosic polymer. In yet another embodiment, the matrixmaterial comprises an amphiphilic, ionizable polymer.

In one embodiment, the matrix material is biodegradable, meaning thatthe matrix material will degrade over time. By “degrade” is meant thatin a use environment, the matrix material is broken down into smallerspecies that can be absorbed, metabolized, or otherwise eliminated orremoved from the environment of use. This degradation can occur throughenzymatic, hydrolytic, oxidative, or other reaction, as is well known inthe art, or by degrading the matrix material into aqueous solublespecies that can readily be removed from the environment of use.

In one embodiment, the composition made by the disclosed processes is inthe form of a solid amorphous dispersion of the active agent and thematrix material.

In another embodiment, the particles comprise a solid amorphousdispersion of the active agent and matrix material consistingessentially of amorphous active agent molecularly dispersed throughoutthe matrix material. In this embodiment, the solid dispersion may beconsidered a “solid solution” of active agent and matrix material. Theterm “solid solution” includes both thermodynamically stable solidsolutions in which the active agent is completely dissolved in thematrix material, as well as homogeneous materials consisting ofamorphous active agent molecularly dispersed throughout the matrixmaterial in amounts greater than the solubility of the active agent inthe matrix material. A dispersion is considered a “solid solution” whenit displays a single glass-transition temperature when analyzed bydifferential scanning calorimetry (DSC). In one embodiment, theparticles have at least one Tg due to the amorphous character of thematrix material. In another embodiment, at least 90 wt % of the activeagent in the particles is amorphous. In yet another embodiment, theactive agent is amorphous and molecularly dispersed in a portion of oneor more of the matrix materials, while the remaining portion of thematrix materials is present as a separate phase. This separate phasematrix material may be amorphous, crystalline, or a mixture of bothamorphous and crystalline.

In another embodiment the particles comprise the active agent incrystalline form, which is homogeneously or substantially homogeneouslydistributed in the matrix material. In still another embodiment, theparticles comprise the active agent in amorphous or non-crystallineform, which is homogeneously distributed in the matrix material matrix.In yet another embodiment, the particles comprise a mixture of activeagent in crystalline and amorphous forms homogeneously distributed inthe matrix material.

In still another embodiment, the particles comprise a mixture ofactive-agent-rich domains and matrix material-rich domains. The activeagent in the domains may be amorphous, crystalline, or a mixture ofamorphous and crystalline.

In yet another embodiment, the compositions comprise a third componentin addition to the active agent and the matrix material. This thirdcomponent may be any compound or mixture of compounds that facilitatesthe intended use of the disclosed compositions. Exemplary thirdcomponents include, but are not limited to, matrix materials, surfaceactive agents, wetting agents, diluents, fillers, bulking agents,disintegrants, flavors, fragrances, buffering agents, and/or othercomponents known in the art.

Examples 10-11

Active Agent 1 was S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,17-propionate, also known as fluticasone propionate, having thestructure:

Active Agent 1 has a solubility of 0.4 μg/mL in pH 7.4 buffer, and a LogP value of 3.7. The Tg of amorphous Active Agent 1 was determined by DSCto be 84° C. The room temperature (20° C. to 30° C.) solubility ofActive Agent 1 in methanol is 0.3 wt %.

Example 10

A spray-dried dispersion was made using an apparatus similar to thatshown in FIG. 9. A feed suspension was prepared by mixing 3 gm of ActiveAgent 1 and 9 gm of the MG grade of hydroxypropyl methylcelluloseacetate succinate (HPMCAS-MG, AQOAT-MG available from Shin Etsu, Tokyo,Japan) with 88 gm of a methanol solvent. The HPMCAS-MG dissolved in thesolvent, while the active agent remained in suspension. The feedsuspension was maintained at ambient temperature, 20° C. to 30° C., withstifling in a pressure pot to prevent settling of the particles ofActive Agent 1. The total solids content of the feed suspension was 12wt %.

The feed suspension in the pressure pot was pressurized to 245 psig anddirected at a rate of 26 gm/min to a tube-in-shell heat exchanger.Heating fluid at 160° C. was circulated in a countercurrent mannerthrough the heat exchanger. The spray solution exiting the heatexchanger was at a temperature, T₂, of 120° C., and all of the activeagent and matrix material were dissolved in the spray solution. Theaverage residence time of the spray solution in the heat exchanger wasless than 60 seconds. The total time the spray solution was at atemperature of 120° C. was less than 80 seconds. Thus, the elapsed timefrom the time the spray solution exited the heat exchanger to the timeit exited the pressure nozzle was 20 seconds. The temperature of thenozzle was 120° C.

The spray solution was delivered to the spray-drying chamber where itwas atomized using a Schlick 2.0 pressure nozzle (Diisen-Schlick GmbH ofUntersiemau, Germany). The spray solution was atomized into dropletswithin the spray-drying chamber, while simultaneously mixing thedroplets with a nitrogen drying gas which was introduced to the dryingchamber at a temperature of 140° C. and at a flow rate of 520 gm/min,resulting in the formation of solid particles.

The solid particles, along with the evaporated solvent and the dryinggas, were directed to a cyclone separator, where the solid particleswere collected. The particles were subsequently dried in a vacuumchamber at 0.15 atm for 2 to 3 hours to remove residual methanol fromthe particles.

The resulting particles had 25 wt % Active Agent 1 in HPMCAS-MG.

Control 1

As a control, a 25 wt % Active Agent 1 in HPMCAS-MG composition was madeusing a conventional ambient-temperature spray-drying process. ForControl 1, a feed solution was formed by dissolving 0.45 gm of ActiveAgent 1 and 1.35 gm of HPMCAS-MG in 179.7 gm methanol. Both the activeagent and the matrix material completely dissolved in the methanol atambient temperature. The total solids content of this solution was 1.0wt %.

This solution was spray dried using the same apparatus as described forExample 1, except that the heat exchanger was bypassed, such that thespray solution was not heated prior to atomization. All other operatingvariables were nominally the same as described in Example 1.

Control 2

As a second control, a feed suspension similar to that formed forExample 1 was prepared and then spray dried without heating the spraysolution. The feed suspension consisted of 2.25 gm of Active Agent 1,6.75 gm of HPMCAS-MG, and 66 gm of methanol, resulting in a feedsuspension containing 12 wt % solids. Because the feed was a suspensionrather than a solution, a two-fluid nozzle was used (manufactured bySpray Systems, Wheaton, Ill.) to avoid clogging.

The feed suspension was spray dried using the same apparatus asdescribed for Example 1, except that the heat exchanger was bypassed,such that the spray solution was not heated prior to atomization, and atwo-fluid nozzle was used for atomization of the feed. All otheroperating variables were nominally the same as described in Example 1.

Analysis of Compositions from Example 10, Control 1, and Control 2

Samples of the compositions of Example 10, Control 1, and Control 2 wereanalyzed by powder X-ray diffraction using an AXS D8 Advance PXRDmeasuring device (Bruker, Inc. of Madison, Wis.). Samples (approximately100 mg) were packed in Lucite sample cups fitted with Si(511) plates asthe bottom of the cup to give no background signal. Samples were spun inthe φ plane at a rate of 30 rpm to minimize crystal orientation effects.The x-ray source (KCu_(α), λ=1.54 Å) was operated at a voltage of 45 kVand a current of 40 mA. Data for each sample were collected over aperiod of 27 minutes in continuous detector scan mode at a scan speed of1.8 seconds/step and a step size of 0.04°/step. Diffractograms werecollected over the 28 range of 4° to 40°.

FIG. 11 shows the results of this analysis. The composition of Example10, made using a concentrated feed suspension and a heat exchanger toincrease the feed temperature according to the disclosed processes,showed an amorphous halo, indicating the active agent in the compositionwas amorphous. Likewise, the composition of Control 1, made using aconventional spray-drying process using a dilute spray solution ofactive agent and matrix material dissolved in a solvent at ambienttemperature, also showed only an amorphous halo. However, thecomposition of Control 2, made using a concentrated feed suspension butnot heated, showed a large number of well-defined peaks, indicating thepresence of crystalline active agent in the composition.

This analysis shows that the compositions of Example 10 and Control 1had similar properties. However, because the spray solution for Example1 contained 12 wt % solids, while the spray solution for Control 1 onlycontained 1 wt % solids, certain embodiments of the disclosed processes(Example 10) had a throughput that was 12-fold greater than that of theconventional spray-drying process.

Example 11

A spray-dried dispersion is made using an apparatus similar to thatshown in FIG. 9 using the procedures outlined in Example 11, except thatthe flash nozzle of FIG. 10 is used. The resulting particles consist of25 wt % Active Agent 1 in HPMCAS.

In one embodiment, the disclosed spray-drying processes comprisesdelivering a spray solution comprising an active agent and a matrixmaterial in an organic solvent to a spray-drying apparatus, atomizingthe spray solution into droplets within the spray-drying apparatus via anozzle to remove at least a portion of the organic solvent from thedroplets to form a plurality of particles, and collecting the particles.The spray solution is delivered to the nozzle at a temperature T₃. Thespray solution is formed by forming a feed suspension comprising theactive agent, the matrix material and the organic solvent, wherein thefeed suspension is at a temperature T₁, and directing the feedsuspension to a heat exchanger, thereby increasing the temperature ofthe feed suspension to a temperature T₂. Temperature T₂ is greater thantemperature T₁, and the spray solution is at a pressure that is greaterthan the vapor pressure of the solvent at temperature T₂, such that theactive agent and the matrix material are soluble in the solvent attemperature T₂. In one embodiment, the temperature T₂ is greater thanthe ambient-pressure boiling point of the solvent.

In any or all of the disclosed embodiments, the active agent and thematrix material may be soluble in the solvent at temperature T₃. In anyor all of the disclosed embodiments, the spray solution may be atomizedusing a flash nozzle.

In any or all of the disclosed embodiments, the temperature T₂ may be atleast 100° C. In any or all of the disclosed embodiments, the spraysolution may be at temperature T₂ for less than 10 minutes.Alternatively, the spray solution may be at temperature T₂ for less than5 minutes.

In any or all of the disclosed embodiments, the organic solvent isselected from methanol, ethanol, n-propanol, isopropanol, butanolacetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate,propyl acetate, tetrahydrofuran, acetonitrile, methylene chloride,toluene, 1,1,1-trichloroethane, and mixtures thereof. In certainembodiments, the organic solvent is selected from the group consistingof methanol, ethanol, n-propanol, isopropanol, butanol acetone, methylethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate,tetrahydrofuran, acetonitrile, methylene chloride, toluene,1,1,1-trichloroethane, and mixtures thereof. In any or all of thedisclosed embodiments, the organic solvent may contain less than 50 wt %water.

In any or all of the disclosed embodiments, the particles may have amass median aerodynamic diameter ranging from 0.5 μm to 10 μm. In any orall of the disclosed embodiments, the particles may have an averagediameter of greater than 10 μm.

In any or all of the disclosed embodiments, the matrix material maycomprise a polymer. In some embodiments, the particles comprise a solidamorphous dispersion of the active agent in the polymer.

Also disclosed are embodiments of products made by any or all of theabove processes. In some embodiments, the product comprises a solidamorphous dispersion of the active agent and the polymer.

An embodiment of a process for producing a composition comprises forminga feed suspension comprising an active agent, a matrix material and anorganic solvent, wherein the feed suspension is at a temperature T₁,forming a spray solution by directing the feed suspension to a heatexchanger, thereby increasing the temperature of the feed suspension toa temperature T₂, wherein temperature T₂ is greater than temperature T₁,the spray solution is at a pressure that is greater than the vaporpressure of the solvent at temperature T₂, and the active agent and thematrix material are soluble in the solvent at temperature T₂, directingthe spray solution to a spray-drying apparatus, the spray-dryingapparatus comprising a drying chamber, a nozzle for atomizing the spraysolution into droplets, and a source of heated drying gas for removingat least a portion of the organic solvent from the droplets, atomizingthe spray solution into droplets in the drying chamber by the nozzle,wherein the spray solution is delivered to the nozzle at a temperatureT₃, contacting the droplets with the heated drying gas to remove atleast a portion of the organic solvent from the droplets to form aplurality of particles comprising the active agent and the matrixmaterial, and collecting the particles. In some embodiments, thetemperature T₂ is greater than the ambient-pressure boiling point of thesolvent.

In the disclosed embodiments, the active agent and the matrix materialmay be soluble in the solvent at temperature T₃. Alternatively, theactive agent or the matrix material may not be soluble in the solvent attemperature T₃.

The various methods and systems, or portions thereof, described withreference to FIGS. 1-8 can also be used in combination with the methodsand systems, or portions thereof, described with reference to FIGS.9-11. For example, as shown in FIG. 12, a spray-drying apparatus 210includes a drying chamber 40 of the type disclosed in FIGS. 1-8 and aheating device 30 of the type disclosed in FIGS. 9-11. The structure andoperation of spray-drying apparatus 210 are described below; however, itshould be understood that certain aspects of spray-drying apparatus 210are common to other spray-drying apparatuses described herein andtherefore the description of those aspects may not be repeated.Accordingly, unless one of ordinary skill in the art would understandotherwise in view of FIG. 12 and its related description, thedescriptions herein of other embodiments of spray-drying apparatuses arealso generally applicable to spray-drying apparatus 210.

As shown in FIG. 12, apparatus 210 includes a feed suspension tank 20, aheat exchanger 30, a drying chamber 40, a nozzle 50, and aparticle-collection means 60. The feed suspension in the feed suspensiontank 20 can be delivered to a pump 24, which directs the feed suspensionto a heating device, such as heat exchanger 30. Heat exchanger 30 has afeed suspension inlet 26, a spray solution outlet 36, a heating fluidinlet 32, and a heating fluid outlet 34. The feed suspension enters heatexchanger 30 through the feed suspension inlet 26 at temperature T₁, andexits as a spray solution through the spray solution outlet 36 attemperature T₂.

In the embodiment shown in FIG. 12, the spray solution is directed intoa drying chamber 40 of the type described with reference to FIGS. 1-8.The spray solution enters nozzle 50, which atomizes the spray solutioninto droplets 44. The drying chamber 40 has a first end 70, a second end72, and at least one side wall 48 extending between the first end 70 andsecond end 72 to define an interior of the drying chamber 40. As shownin FIG. 12, nozzle 50 can be positioned at first end 70 and at least aportion of the side wall(s) 48 can extend away from a center axis of thedrying chamber 40 at a first angle relative to the center axis (see,e.g., FIG. 2).

The first angle can be between 5 degrees and 45 degrees. In addition, insome embodiments, a ratio of the length between the first and secondends of the drying chamber to a maximum width between opposing internalsurfaces of the interior of the drying chamber 40 can be at least 5to 1. Nozzle 50 is configured to atomize the spray solution into thedrying chamber 40 at a maximum spray pattern angle relative to thecenter axis of the drying chamber 40 that is less than 45 degrees.Additional suitable structures and more specific and/or differentsuitable ranges are disclosed in more detail above in connection withthe embodiments shown in FIGS. 1-11.

In some embodiments, an active agent and a matrix material can becombined with a solvent in the feed suspension tank 20 to form a feedsuspension. As described herein, the solvent can be an organic solvent.

In some embodiments, nozzle 50 can comprise a flash nozzle as describedabove with respect to FIG. 10 and as described below in Example 12. Theflash nozzle utilizes a pressure drop that induces cavitation in thespray solution prior to exiting the nozzle orifice to induce dropletformation. A sweep gas around the orifice is used to eliminate or reducesolids build-up during operation.

By combining elements of a spray dryer that is capable of exhibit lowresidence times for spray-dried particles (i.e., FIGS. 1-8) with anelevated temperature spray dryer (i.e., FIGS. 9-11), the resultingspray-drying apparatus 210 and methods of using the same can reduceunnecessary circulation of spray-drying particles, minimize residencetimes in the drying chamber, and allow spray solutions to be elevated totemperatures that can improve various aspects of the spray solution,such as improved solubility by heating the spray solution to atemperature above which most or all components of the solution aredissolvable.

Example 12

A composition was made using an apparatus similar to that shown in FIG.12. A 5 wt % feed suspension was prepared by mixing 75 g of dextranhaving a starting average molecular weight of 5000 Daltons, thensubstituted with propionate and succinate groups (D5PS), with 1425 g ofacetone in a feed suspension tank. The feed suspension was maintained atambient temperature with stifling to prevent settling of the particles.The feed suspension was pumped to a heat exchanger, entering the heatexchanger at ambient temperature, and exiting the heat exchanger at 135°C. as the spray solution.

The spray solution was delivered to the spray drying apparatus similarto that shown in FIG. 12. The spray solution was delivered to the spraydrier at a rate of 39 g/min at a pressure of 735 psig. The spraysolution was atomized using a flash nozzle having an inside diameter of170 μm, an outside diameter of 1588 μm, and a length of 50 mm, insertedinto a 0.3-mm diameter tube, similar to the nozzle shown in FIG. 10;nitrogen was flowing through the outer tube at a flow rate such that thenitrogen pressure in the outer tube was 10 psig. Nitrogen drying gasentered the drying chamber at a flow rate of 1630 g/min and an inlettemperature of 67° C. The evaporated solvent and drying gas exited thespray drier at a temperature of 47° C. The resulting composition wascollected in a cyclone.

The particles were characterized using a Malvern Particle Size Analyzer,available from Malvern Instruments Ltd. of Framingham, Mass. The meandiameter is reported as D(3,2) (the sum of diameters cubed over the sumof diameters squared). The data obtained includes D₁₀, the diametercorresponding to the diameter of particles that make up 10% of the totalvolume containing particles of equal or smaller diameter, D₅₀, and D₉₀.Another parameter is “Span,” a dimensionless parameter indicative of theuniformity of the particle size distribution, defined as

${Span} = \frac{D_{90} - D_{10}}{D_{50}}$Generally, the lower the Span, the more narrow the particle sizedistribution, resulting in improved flow characteristics. The results ofthe particle characterization for Example 12 are shown in Table 6.

Examples 13-15

In Examples 13-15, particles were spray-dried as described in Example12, with the following exceptions. For Example 13, a flash nozzle wasused having an inside diameter of 250 μm, an outside diameter of 1588μm, and a length of 50 mm, inserted into a 0.3-mm diameter tube;nitrogen was flowing through the outer tube at a flow rate such that thenitrogen pressure in the outer tube was 40 psig. The feed solution flowwas 123 g/min at a pressure of 730 psig, and the nitrogen drying gasflow was 1350 g/min at 110° C. The evaporated solvent and drying gasexited the spray drier at a temperature of 48° C.

For Example 14, a flash nozzle was used having an inside diameter of 380μm, an outside diameter of 1588 μm, and a length of 50 mm, inserted intoa 0.3-mm diameter tube; nitrogen was flowing through the outer tube at aflow rate such that the nitrogen pressure in the outer tube was 10 psig.The feed solution flow was 208 g/min at a pressure of 680 psig, and thedrying gas nitrogen flow was 1370 g/min at 100° C. The evaporatedsolvent and drying gas exited the spray drier at a temperature of 46° C.

For Example 15, a 10 wt % spray suspension was made by mixing 30.3 g ofD5PS, with 273 g of acetone. The flash nozzle of Example 14 was used,the feed solution flow was 200 g/min at a pressure of 605 psig, and thedrying gas nitrogen flow was 1650 g/min at 114° C. The evaporatedsolvent and drying gas exited the spray drier at a temperature of 47° C.

The results of the particle characterization analysis for the particlesformed in Examples 12-15 are shown in Table 6.

TABLE 6 Particle Properties Example D(3, 2) (μm) D₁₀ (μm) D₅₀ (μm) D₉₀(μm) Span 12 2.1 1.3 2.4 4.6 1.4 13 2.2 1.3 2.5 4.6 1.4 14 2.3 1.3 2.65.3 1.5 15 2.3 1.3 2.7 6.1 1.8

In view of the many possible embodiments to which the principles of thedisclosed invention may be applied, it should be recognized that theillustrated embodiments are only preferred examples of the invention andshould not be taken as limiting the scope of the invention. Rather, thescope of the invention is defined by the following claims. We thereforeclaim as our invention all that comes within the scope and spirit ofthese claims.

We claim:
 1. A method of spray drying, comprising: forming a pluralityof droplets by atomizing a spray solution using a nozzle positioned atthe first end of the drying chamber, the drying chamber furthercomprising a second end and at least one side wall extending between thefirst and second ends to define an interior of the drying chamber andhaving a center axis, wherein at least a portion of the at least oneside wall that surrounds the nozzle at the first end of the dryingchamber extends away from the center axis at a first angle relative tothe center axis, the first angle being at least 5° but less than 45°,and wherein a ratio of the length between the first and second ends to amaximum width between opposing internal surfaces of the interior of thedrying chamber is at least 5 to 1; delivering the plurality of dropletsinto the drying chamber; delivering drying gas into the drying chamberto at least partially dry the plurality of droplets to form a pluralityof particles; and directing the plurality of particles out of the dryingchamber; wherein the spray solution is initially at a temperature T₁ andis directed to a heat exchanger to increase the temperature of the spraysolution to temperature T₂ prior to atomization of the spray solution,wherein temperature T₂ is greater than temperature T₁; wherein saidspray solution comprises at least one active agent, at least oneexcipient, and at least one solvent.
 2. The method of claim 1 whereinsaid excipient comprises synthetic polymers, polysaccharides,derivatized polysaccharides, sugars, sugar alcohols, organic acids,salts of organic acids, inorganic salts, proteins, amino acids,phospholipids, and pharmaceutically acceptable salt forms, derivatives,and mixtures thereof.
 3. The method of claim 1 wherein said excipientcomprises polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO),poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates,polyoxyethylene alkyl ethers, polyoxyethylene castor oils,polycaprolactam, polylactic acid, polyglycolic acid,poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran,maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate,heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethylethylcellulose (CMEC), hydroxypropyl methylcellulose acetate succinate(HPMCAS), ethyl cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, dextran polymer derivatives, trehalose,glucose, sucrose, raffinose, lactose, mannitol, erythritol, xylitol,polydextrose, oleic acid, citric acid, tartaric acid, edetic acid, malicacid, sodium citrate, sodium bicarbonate, albumin, gelatin, acacia,casein, caseinate, glycine, leucine, serine, alanine, isoleucine,trileucine, lecithin, phosphatidylcholine, and pharmaceuticallyacceptable forms, derivatives, and mixtures thereof.
 4. The method ofclaim 1 wherein the excipient is selected from lactose, mannitol,trehalose, sucrose, citric acid, leucine, glycine, and pharmaceuticallyacceptable salt forms, derivatives, and mixtures thereof.
 5. The methodof claim 1, wherein the droplets are delivered into the drying chamberat a maximum spray pattern angle relative to the center axis of lessthan 45°.
 6. The method of claim 1, wherein the first angle is at least5° but less than 30° relative to the center axis.
 7. The method of claim1, wherein the nozzle is configured to atomize a liquid into the dryingchamber at a maximum spray pattern angle relative to the center axis ofless than 30°.
 8. The method of claim 1, wherein the first angle is atleast 5° but less than 20° relative to the center axis.
 9. The method ofclaim 1, wherein the droplets are delivered into the drying chamber at amaximum spray pattern angle relative to the center axis of less than20°.
 10. The method of claim 1, wherein said composition is a solidamorphous dispersion of said active agent and said excipient.
 11. Themethod of claim 1, wherein said particles have an average diameterranging from 0.5 μm to 500 μm.
 12. The method of claim 1, wherein saidparticles have an average diameter ranging from 0.5 μm to 100 μm. 13.The method of claim 1, wherein said particles have an average diameterof less than 10 μm.
 14. The method of claim 1, wherein said particleshave an average diameter of greater than 10 μm.
 15. The method of claim1, wherein said active agent is selected from at least one drug,medicament, pharmaceutical, therapeutic agent, nutraceutical, nutrient,or other compounds.
 16. The method of claim 15, wherein said activeagent is selected from a small molecule, having a molecular weight of2000 Daltons or less.
 17. The method of claim 15, wherein said activeagent is selected from proteins, antibodies, antibody fragments,peptides, oligonucleotides, vaccines, and various derivatives of suchmaterials.
 18. The method of claim 15, wherein said active agent is amixture of a small molecule, having a molecular weight of 2000 Daltonsor less and a protein, antibodies, antibody fragments, peptides,oligonucleotides, vaccines, and various derivatives of such materials.19. The method of claim 15, wherein said active agent comprises two ormore active agents.
 20. The method of claim 1, wherein said solvent isselected from water, methanol, ethanol, n-propanol, isopropanol,butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, propyl acetate, tetrahydrofuran, acetonitrile, methylenechloride, toluene, 1,1,1-trichloroethane, dimethyl acetamide,dimethylsulfoxide, or mixtures and combinations thereof.